VCV000012130.24 - ClinVar

NM_000063.6(C2):c.954G>C (p.Glu318Asp)

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.

(12)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000063.6(C2):c.954G>C (p.Glu318Asp)

Variation ID: 12130 Accession: VCV000012130.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.33 6: 31936027 (GRCh38) [ NCBI UCSC ] 6: 31903804 (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	Oct 31, 2013	Sep 29, 2024	Jan 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000063.6:c.954G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000054.2:p.Glu318Asp	missense
NM_001145903.3:c.558G>C	NP_001139375.1:p.Glu186Asp	missense
NM_001178063.3:c.347-1292G>C		intron variant
NM_001282457.2:c.216G>C	NP_001269386.1:p.Glu72Asp	missense
NM_001282458.2:c.867G>C	NP_001269387.1:p.Glu289Asp	missense
NC_000006.12:g.31936027G>C
NC_000006.11:g.31903804G>C
NG_011730.1:g.13539G>C
LRG_26:g.13539G>C
LRG_26t1:c.954G>C
	P06681:p.Glu318Asp

... more HGVS ... less HGVS

Protein change

E318D, E72D, E186D, E289D

Other names

C2, GLU318ASP

Canonical SPDI

NC_000006.12:31936026: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.

0.02975 (C)

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

1000 Genomes Project 30x 0.02904

1000 Genomes Project 0.02975

Trans-Omics for Precision Medicine (TOPMed) 0.03030

The Genome Aggregation Database (gnomAD) 0.03307

Exome Aggregation Consortium (ExAC) 0.03896

Links

UniProtKB: P06681#VAR_019158 OMIM: 613927.0004 dbSNP: rs9332739 ClinGen: CA121908 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.
C2		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	281	390
C2-AS1	-	-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38	-	59

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.
Age related macular degeneration 14	Likely benign (2)	criteria provided, single submitter	Apr 27, 2017	RCV000012913.8
Complement component 2 deficiency	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	May 28, 2019	RCV000304426.6
not specified	Benign (4)	criteria provided, single submitter	Mar 28, 2016	RCV000454375.9
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV001516299.9
Age related macular degeneration 14 Complement component 2 deficiency	Likely benign (1)	criteria provided, single submitter	Apr 9, 2022	RCV002496332.1

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.
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Complement component 2 deficiency Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137072.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Age related macular degeneration 14 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000461949.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 9670930 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Complement component 2 deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000461950.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Jul 20, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001882547.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 9670930, 22610944, 25525159, 32113979, 16936732, 16518403)
Likely benign (Apr 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Complement component 2 deficiency Age related macular degeneration 14 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002806298.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely benign (-)	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: SCV005225529.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Mar 28, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000538519.1 First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017	Publications: PubMed (1) PubMed: 9670930 Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF (less) Method: Genome/Exome Filtration
Benign (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001724564.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957275.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Sep 01, 2006)	no assertion criteria provided Method: literature only	MACULAR DEGENERATION, AGE-RELATED, 14, REDUCED RISK OF Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033154.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 31, 2013	Publications: PubMed (2) PubMed: 16518403‚ 16936732 Comment on evidence: In approximately 900 individuals with ARMD (ARMD14; 615489) and approximately 400 controls, Gold et al. (2006) found a significant association between haplotype H10, consisting of … (more) In approximately 900 individuals with ARMD (ARMD14; 615489) and approximately 400 controls, Gold et al. (2006) found a significant association between haplotype H10, consisting of the L9H variant (138470.0003) of the CFB gene and the glu318-to-asp (E318D; rs9332739) variant of the C2 gene, and a reduced risk of ARMD. Maller et al. (2006) replicated the association of the L9H variant of CFB and the E318D variant of C2 with risk of ARMD, noting that although this pair of SNPs has minor alleles that confer an equivalent protective effect, they found these effects to be independent and distinct. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001739738.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001928698.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF

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:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration.	Maller J	Nature genetics	2006	PMID: 16936732
Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration.	Gold B	Nature genetics	2006	PMID: 16518403
A novel type II complement C2 deficiency allele in an African-American family.	Zhu ZB	Journal of immunology (Baltimore, Md. : 1950)	1998	PMID: 9670930

Text-mined citations for rs9332739 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000063.6(C2):c.954G>C (p.Glu318Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs9332739 ...