VCV000004570.22 - ClinVar

NM_031885.5(BBS2):c.72C>G (p.Tyr24Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_031885.5(BBS2):c.72C>G (p.Tyr24Ter)

Variation ID: 4570 Accession: VCV000004570.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q13 16: 56519791 (GRCh38) [ NCBI UCSC ] 16: 56553703 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 6, 2017	Oct 8, 2024	Mar 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_031885.5:c.72C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_114091.4:p.Tyr24Ter	nonsense
NM_001377456.1:c.72C>G	NP_001364385.1:p.Tyr24Ter	nonsense
NR_165293.1:n.234C>G		non-coding transcript variant
NR_165294.1:n.234C>G		non-coding transcript variant
NR_165295.1:n.234C>G		non-coding transcript variant
NR_165296.1:n.234C>G		non-coding transcript variant
NR_165297.1:n.234C>G		non-coding transcript variant
NC_000016.10:g.56519791G>C
NC_000016.9:g.56553703G>C
NG_009312.2:g.5234C>G

... more HGVS ... less HGVS

Protein change

Y24*

Other names

Canonical SPDI

NC_000016.10:56519790:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00005

Trans-Omics for Precision Medicine (TOPMed) 0.00005

Exome Aggregation Consortium (ExAC) 0.00006

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA116926 OMIM: 606151.0003 dbSNP: rs121908175 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BBS2		-	-	GRCh38 GRCh37	1142	1180

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
BARDET-BIEDL SYNDROME 2/6, DIGENIC	Pathogenic (1)	no assertion criteria provided	Sep 21, 2001	RCV000004832.5
Bardet-Biedl syndrome 2	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 19, 2024	RCV000412476.8
Bardet-Biedl syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 20, 2024	RCV000589350.9
Bardet-Biedl syndrome 2 Retinitis pigmentosa 74	Pathogenic (1)	criteria provided, single submitter	Sep 7, 2021	RCV000762970.4
Retinitis pigmentosa	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787792.1
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Sep 18, 2017	RCV001074960.3
BBS2-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 23, 2024	RCV004732529.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 10, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Bardet-Biedl syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699658.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (3) PubMed: 20177705‚ 20498079‚ 11567139 Comment: Variant summary: The BBS2 c.72C>G (p.Tyr24X) variant results in a premature termination codon, predicted to cause a truncated or absent BBS2 protein due to nonsense … (more) Variant summary: The BBS2 c.72C>G (p.Tyr24X) variant results in a premature termination codon, predicted to cause a truncated or absent BBS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 7/116822 control chromosomes at a frequency of 0.0000599, which does not exceed the estimated maximal expected allele frequency of a pathogenic BBS2 variant (0.0008452). This variant has been reported in multiple BBS patients in homozygous or compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Sep 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 2 Retinitis pigmentosa 74 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893411.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Likely pathogenic (Jun 15, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Bardet-Biedl syndrome 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV000924501.1 First in ClinVar: Jun 23, 2019 Last updated: Jun 23, 2019	Comment: The heterozygous p.Tyr24Ter variant was identified by our study in the compound heterozygous state, with a VUS, in one individual with Bardet-Biedl syndrome. This variant … (more) The heterozygous p.Tyr24Ter variant was identified by our study in the compound heterozygous state, with a VUS, in one individual with Bardet-Biedl syndrome. This variant has been identified in <0.01% (12/125738) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908175). Loss of function of the BBS2 gene is an established disease mechanism in autosomal recessive Bardet-Biedl syndrome 2, and this is a loss of function variant. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic. (less) Clinical Features: Rod-cone dystrophy (present) , Polydactyly (present) , Obesity (present)
Pathogenic (Sep 18, 2017)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001240567.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Jan 20, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Bardet-Biedl syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000940175.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 11285252‚ 20177705‚ 24608809‚ 26518167‚ 11567139‚ 21344540 Comment: This sequence change creates a premature translational stop signal (p.Tyr24) in the BBS2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Tyr24) in the BBS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252, 20177705, 24608809, 26518167). This variant is present in population databases (rs121908175, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 11567139, 21344540). ClinVar contains an entry for this variant (Variation ID: 4570). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 19, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004213988.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Sep 21, 2001)	no assertion criteria provided Method: literature only	BARDET-BIEDL SYNDROME 2/6, DIGENIC Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025008.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 28, 2017	Publications: PubMed (1) PubMed: 11567139 Comment on evidence: Katsanis et al. (2001) identified homozygosity for a tyrosine-to-termination substitution at codon 24 (Y24X) of the BBS2 gene in 2 unrelated patients with Bardet-Biedl syndrome … (more) Katsanis et al. (2001) identified homozygosity for a tyrosine-to-termination substitution at codon 24 (Y24X) of the BBS2 gene in 2 unrelated patients with Bardet-Biedl syndrome (BBS2; 615981). One of those patients carried an additional mutation in the BBS6 gene (ala242-to-ser; see 604896.0001). The Y24X mutation was also found in compound heterozygosity with the gln59-to-ter mutation (606151.0004) in a patient who carried a third mutation in the MKKS gene (Q147X; 604896.0012). (less)
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926802.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Bardet-Biedl syndrome type 2 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001458478.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (Nov 03, 2016)	no assertion criteria provided Method: clinical testing	Bardet-Biedl syndrome 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000486607.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 23, 2019	Publications: PubMed (1) PubMed: 21344540
Pathogenic (Jul 23, 2024)	no assertion criteria provided Method: clinical testing	BBS2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005367673.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The BBS2 c.72C>G variant is predicted to result in premature protein termination (p.Tyr24). This variant has been reported in the homozygous or compound heterozygous states … (more) The BBS2 c.72C>G variant is predicted to result in premature protein termination (p.Tyr24). This variant has been reported in the homozygous or compound heterozygous states in individuals with Bardet-Biedl syndrome (Katsanis et al. 2001. PubMed ID: 11567139; Supplementary Data, Stone et al. 2017. PubMed ID: 28559085) and was identified in another individual with retinitis pigmentosa, although no second variant was described (Supplementary Data, Jespersgaard et al. 2019. PubMed ID: 30718709). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in BBS2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Comment:

Variant summary: The BBS2 c.72C>G (p.Tyr24X) variant results in a premature termination codon, predicted to cause a truncated or absent BBS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 7/116822 control chromosomes at a frequency of 0.0000599, which does not exceed the estimated maximal expected allele frequency of a pathogenic BBS2 variant (0.0008452). This variant has been reported in multiple BBS patients in homozygous or compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

The heterozygous p.Tyr24Ter variant was identified by our study in the compound heterozygous state, with a VUS, in one individual with Bardet-Biedl syndrome. This variant has been identified in <0.01% (12/125738) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908175). Loss of function of the BBS2 gene is an established disease mechanism in autosomal recessive Bardet-Biedl syndrome 2, and this is a loss of function variant. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Tyr24*) in the BBS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252, 20177705, 24608809, 26518167). This variant is present in population databases (rs121908175, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 11567139, 21344540). ClinVar contains an entry for this variant (Variation ID: 4570). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The BBS2 c.72C>G variant is predicted to result in premature protein termination (p.Tyr24*). This variant has been reported in the homozygous or compound heterozygous states in individuals with Bardet-Biedl syndrome (Katsanis et al. 2001. PubMed ID: 11567139; Supplementary Data, Stone et al. 2017. PubMed ID: 28559085) and was identified in another individual with retinitis pigmentosa, although no second variant was described (Supplementary Data, Jespersgaard et al. 2019. PubMed ID: 30718709). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in BBS2 are expected to be pathogenic. This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
Targeted multi-gene panel testing for the diagnosis of Bardet Biedl syndrome: Identification of nine novel mutations across BBS1, BBS2, BBS4, BBS7, BBS9, BBS10 genes.	Ece Solmaz A	European journal of medical genetics	2015	PMID: 26518167
Comprehensive molecular diagnosis of Bardet-Biedl syndrome by high-throughput targeted exome sequencing.	Xing DJ	PloS one	2014	PMID: 24608809
BBS genotype-phenotype assessment of a multiethnic patient cohort calls for a revision of the disease definition.	Deveault C	Human mutation	2011	PMID: 21344540
Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome.	Zaghloul NA	Proceedings of the National Academy of Sciences of the United States of America	2010	PMID: 20498079
Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease.	Muller J	Human genetics	2010	PMID: 20177705
Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder.	Katsanis N	Science (New York, N.Y.)	2001	PMID: 11567139
Positional cloning of a novel gene on chromosome 16q causing Bardet-Biedl syndrome (BBS2).	Nishimura DY	Human molecular genetics	2001	PMID: 11285252

Text-mined citations for rs121908175 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_031885.5(BBS2):c.72C>G (p.Tyr24Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908175 ...