VCV000348114.21 - ClinVar

NM_001199397.3(NEK1):c.1388C>T (p.Ala463Val)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Benign/Likely benign

7 out of 9 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_001199397.3(NEK1):c.1388C>T (p.Ala463Val)

Variation ID: 348114 Accession: VCV000348114.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q33 4: 169555974 (GRCh38) [ NCBI UCSC ] 4: 170477125 (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 6, 2016	Feb 16, 2025	Feb 3, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001199397.3:c.1388C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001186326.1:p.Ala463Val	missense
NM_001199398.3:c.1388C>T	NP_001186327.1:p.Ala463Val	missense
NM_001199399.3:c.1313C>T	NP_001186328.1:p.Ala438Val	missense
NM_001199400.3:c.1388C>T	NP_001186329.1:p.Ala463Val	missense
NM_001374418.1:c.1388C>T	NP_001361347.1:p.Ala463Val	missense
NM_001374419.1:c.1388C>T	NP_001361348.1:p.Ala463Val	missense
NM_001374420.1:c.1337C>T	NP_001361349.1:p.Ala446Val	missense
NM_001374421.1:c.1262C>T	NP_001361350.1:p.Ala421Val	missense
NM_012224.4:c.1388C>T	NP_036356.1:p.Ala463Val	missense
NR_164630.1:n.1902C>T		non-coding transcript variant
NC_000004.12:g.169555974G>A
NC_000004.11:g.170477125G>A
NG_027982.1:g.61654C>T
	Q96PY6:p.Ala463Val

... more HGVS ... less HGVS

Protein change

A463V, A438V, A421V, A446V

Other names

Canonical SPDI

NC_000004.12:169555973:G:A

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.

0.01617 (A)

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

1000 Genomes Project 30x 0.01827

1000 Genomes Project 0.01617

The Genome Aggregation Database (gnomAD), exomes 0.03578

Trans-Omics for Precision Medicine (TOPMed) 0.03716

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.04257

Exome Aggregation Consortium (ExAC) 0.03513

The Genome Aggregation Database (gnomAD) 0.03694

Links

ClinGen: CA3137754 UniProtKB: Q96PY6#VAR_040905 dbSNP: rs34540355 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.
NEK1		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	886	959

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.
not specified	Benign (2)	criteria provided, single submitter	Apr 26, 2016	RCV000428150.3
Short-rib thoracic dysplasia 6 with or without polydactyly	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Feb 3, 2025	RCV000540144.15
not provided	Likely benign (2)	criteria provided, single submitter	-	RCV001573270.2
Connective tissue disorder	Benign (1)	criteria provided, single submitter	May 17, 2022	RCV002278576.3

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.
Benign (Apr 26, 2016) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000516281.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Likely benign (May 13, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Short-rib thoracic dysplasia 6 with or without polydactyly Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743657.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017
Benign (Sep 21, 2015) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Short-rib thoracic dysplasia 6 with or without polydactyly Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744994.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017
Benign (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Short-rib thoracic dysplasia 6 with or without polydactyly Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000448565.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (May 17, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Connective tissue disorder Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002566926.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Likely benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005256730.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Feb 03, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Short-rib thoracic dysplasia 6 with or without polydactyly Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000627781.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 16, 2025
Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798870.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001923497.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs34540355 ...

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 08, 2025

ClinVar Genomic variation as it relates to human health

NM_001199397.3(NEK1):c.1388C>T (p.Ala463Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs34540355 ...