VCV001327119.4 - ClinVar

NM_004766.3(COPB2):c.1237_1238del (p.Lys413fs)

Germline

Classification

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Uncertain significance
Uncertain significance (1)

1 out of 2 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004766.3(COPB2):c.1237_1238del (p.Lys413fs)

Variation ID: 1327119 Accession: VCV001327119.4

Type and length

Deletion, 2 bp

Location

Cytogenetic: 3q23 3: 139369512-139369513 (GRCh38) [ NCBI UCSC ] 3: 139088354-139088355 (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	Dec 12, 2021	Apr 13, 2025	Nov 30, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_004766.3:c.1237_1238del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004757.1:p.Lys413fs	frameshift
NR_023350.1:n.1446_1447del		non-coding transcript variant
NC_000003.12:g.139369513_139369514del
NC_000003.11:g.139088355_139088356del

Protein change

K413fs

Other names

p.K413NfsTer3

Canonical SPDI

NC_000003.12:139369511:TTT:T

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.

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

Links

ClinGen: CA2573052095 OMIM: 606990.0002 dbSNP: rs2107801839 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.
COPB2		-	-	GRCh38 GRCh37	238	269

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.
COPB2-related disorder	Uncertain significance (1)	criteria provided, single submitter	Nov 30, 2021	RCV001788996.3
Osteoporosis, childhood- or juvenile-onset, with developmental delay	Pathogenic (1)	no assertion criteria provided	May 24, 2022	RCV002246506.1

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.	Expand all rows Collapse all rows 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.
Uncertain significance (Nov 30, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	COPB2-related condition (Autosomal dominant inheritance)	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV002030293.2 First in ClinVar: Dec 12, 2021 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 34450031 Comment: show This individual has been published in PMID: 34450031. (less) Observation: 1 Collection method: clinical testing Allele origin: de novo Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: de novo Affected status: yes Number of individuals with the variant: 1 Clinical Features: Long philtrum (present) , Anxiety (present) , Osteopenia (present) , Constipation (present) , Cortical dysplasia (present) , Increased susceptibility to fractures (present) , Recurrent infections (present) , Recurrent fractures (present) , Recurrent long bone fractures (present) , Abnormality of bone mineral density (present) , Reduced bone mineral density (present) , Attention deficit hyperactivity disorder (present) , Nephrolithiasis, calcium oxalate (present) , Sleep apnea (present) , Nocturnal enuresis (present) , Seasonal allergy (present) , Abnormal lymphocyte count (present) , Cerebral visual impairment (present) Zygosity: 1 Compound Heterozygote Age: 10-19 years Sex: female Tissue: blood

Pathogenic (May 24, 2022) N Not contributing to aggregate classification	no assertion criteria provided	OSTEOPOROSIS, CHILDHOOD- OR JUVENILE-ONSET, WITH DEVELOPMENTAL DELAY	OMIM Accession: SCV002520540.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022	Publications: PubMed (1) PubMed: 34450031 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In a 9-year-old girl of Caucasian and Native American ancestry (patient 1) with multiple fractures, low bone mineral density, and speech delay with learning disabilities … (more) In a 9-year-old girl of Caucasian and Native American ancestry (patient 1) with multiple fractures, low bone mineral density, and speech delay with learning disabilities (OPDD; 619884), Marom et al. (2021) identified heterozygosity for a de novo 2-bp deletion (c.1237_1238delAA, NM_004766.2) in the COPB2 gene, causing a frameshift predicted to result in a premature termination codon (Lys413AspfsTer3). Sanger sequencing of DNA from the proband and her parents confirmed the de novo origin of the variant, which was not found in the gnomAD database. Sequencing of mRNA on whole blood from the proband demonstrated that the variant results in nonsense-mediated decay; RT-qPCR in patient lymphoblastoid cells supported this finding by showing an approximately 50% reduction in COPB2 expression compared to parents and unaffected sib. (less)

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay.	Marom R	American journal of human genetics	2021	PMID: 34450031

Text-mined citations for rs2107801839 ...

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 Apr 13, 2025