VCV000004745.2 - ClinVar

NM_004667.6(HERC2):c.13272+874T>C

Germline

Classification

no assertion criteria provided. Learn more about how ClinVar calculates review status.

association
association (1)

This classification is based on the single submission received

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_004667.6(HERC2):c.13272+874T>C

Variation ID: 4745 Accession: VCV000004745.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q13.1 15: 28120472 (GRCh38) [ NCBI UCSC ] 15: 28365618 (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 23, 2014	Jan 23, 2014	Feb 13, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NM_004667.6:c.13272+874T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NC_000015.10:g.28120472A>G
NC_000015.9:g.28365618A>G
NG_016355.1:g.206678T>C

Protein change

Other names

IVS86, C/T

Canonical SPDI

NC_000015.10:28120471:A:G

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.

0.17732 (G)

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

1000 Genomes Project 0.17732

1000 Genomes Project 30x 0.17895

Trans-Omics for Precision Medicine (TOPMed) 0.42304

The Genome Aggregation Database (gnomAD) 0.48766

The Genome Aggregation Database (gnomAD) 0.50594

Links

ClinGen: CA117046 OMIM: 605837.0003 dbSNP: rs12913832 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.
HERC2		-	-	GRCh38 GRCh38 GRCh38 GRCh37	1316	1640
LOC128772394	-	-	-	GRCh38 GRCh38 GRCh38	-	159

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.
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	association (1)	no assertion criteria provided	Feb 13, 2018	RCV000005011.5

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.
association (Feb 13, 2018) C Contributing to aggregate classification	no assertion criteria provided	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	OMIM Accession: SCV000025187.2 First in ClinVar: Apr 04, 2013 Last updated: Jan 23, 2014	Publications: PubMed (4) PubMed: 17236130‚ 18172690‚ 18252222‚ 22234890 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 study of the association with eye color (227220) with haplotype-tagging SNPs proximal to intron 1 of the OCA2 gene (611409) that span the … (more) In a study of the association with eye color (227220) with haplotype-tagging SNPs proximal to intron 1 of the OCA2 gene (611409) that span the intergenic region and encompass the 3-prime end of the upstream gene HERC2, Sturm et al. (2008) identified a SNP in intron 86 of HERC2, rs12913832, that was strongly associated with eye color in 3011 European individuals (P = 2 x 10(-78)). Individuals carrying the CC genotype had only a 1% probability of having brown eyes, while those with the TT genotype had an 80% probability. Haplotype analysis combining the 3 SNPs in OCA2 identified by Duffy et al. (2007) (611409.0013) with rs12913832 followed by multiple ordinal logistic regression showed that the HERC2 SNP alone was the best predictor of eye color. Sturm et al. (2008) concluded that the conserved region around rs12913832 represents a regulatory region controlling constitutive expression of OCA2, and that the C allele of rs12913832 leads to decreased expression of OCA2, particularly within iris melanocytes, by abrogation of the binding site for HLTF (603257) that regulates transcription of OCA2. Sturm et al. (2008) also demonstrated that the OCA2 coding SNP R419Q (611409.0012) acts as a penetrance modifier of rs12913832. In a 3-generation Danish family segregating blue and brown eye color, Eiberg et al. (2008) used fine mapping to identify a 166-kb candidate region within the HERC2 gene. Further studies of SNPs within this region among 144 blue-eyed and 45 brown-eyed individuals identified 2 SNPs, rs1129038 and the strongly conserved rs12913832, that showed significant associations with the blue-eyed phenotype (p = 6.2 x 10(-46)). A common founder haplotype containing these SNPs was identified among blue-eyed persons from Denmark, Turkey, and Jordan. In vitro functional expression studies in human colon carcinoma cells showed that what the authors referred to as the 'G' allele of rs12913832, present in blue-eyed individuals, had an inhibitory effect on OCA2 promoter activity. Visser et al. (2012) found that HLTF, LEF1 (153245), and MITF (156845) bound to the enhancer region surrounding rs12913832 in darkly pigmented human melanocytes carrying the T allele of rs12913832. Binding was associated with long-range chromatin looping between the enhancer and the OCA2 promoter, leading to elevated OCA2 expression. In contrast, lightly pigmented melanocytes carrying the C allele of rs12913832 showed reduced enhancer binding, chromatin looping, and OCA2 expression. (less)

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter.	Visser M	Genome research	2012	PMID: 22234890
A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color.	Sturm RA	American journal of human genetics	2008	PMID: 18252222
Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression.	Eiberg H	Human genetics	2008	PMID: 18172690
A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation.	Duffy DL	American journal of human genetics	2007	PMID: 17236130

Text-mined citations for rs12913832 ...

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 May 17, 2025