NM_000063.6:c.954G>C

Variant names:

• chr6-31936027-G-C
• rs9332739
• NM_000063.6:c.954G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000063.6(C2):​c.954G>C​(p.Glu318Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,612,940 control chromosomes in the GnomAD database, including 1,540 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E318E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.034 (108 hom., cov: 31)
  • Exomes 𝑓: 0.043 (1432 hom.)
• Consequence: C2 NM_000063.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: 0.346
• Publications: 171 publications found

Genes affected

C2 (HGNC:1248): (complement C2) Component C2 is a serum glycoprotein that functions as part of the classical pathway of the complement system. Activated C1 cleaves C2 into C2a and C2b. The serine proteinase C2a then combines with complement factor 4b to create the C3 or C5 convertase. Deficiency of C2 has been reported to associated with certain autoimmune diseases and SNPs in this gene have been associated with altered susceptibility to age-related macular degeneration. This gene localizes within the class III region of the MHC on the short arm of chromosome 6. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described in publications but their full-length sequence has not been determined.[provided by RefSeq, Mar 2009]

ENSG00000244255 (HGNC:):

C2-AS1 (HGNC:49464): (C2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063239336).
• BP6: Variant 6-31936027-G-C is Benign according to our data. Variant chr6-31936027-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 12130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000063.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2	NM_000063.6	MANE Select	c.954G>C	p.Glu318Asp	missense	Exon 7 of 18	NP_000054.2
	C2	NM_001282458.2		c.867G>C	p.Glu289Asp	missense	Exon 7 of 18	NP_001269387.1
	C2	NM_001145903.3		c.558G>C	p.Glu186Asp	missense	Exon 5 of 16	NP_001139375.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2	ENST00000299367.10	TSL:1 MANE Select	c.954G>C	p.Glu318Asp	missense	Exon 7 of 18	ENSP00000299367.5
	ENSG00000244255	ENST00000456570.5	TSL:2	c.530-1292G>C		intron	N/A	ENSP00000410815.1
	C2	ENST00000447952.7	TSL:3	c.768G>C	p.Glu256Asp	missense	Exon 6 of 17	ENSP00000391354.3

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 5147 AN: 152144 Hom.: 107 Cov.: 31

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.0225

Gnomad SAS AF: 0.0558

Gnomad FIN AF: 0.0551

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0460

Gnomad OTH AF: 0.0311

GnomAD2 exomes AF: 0.0386 AC: 9529 AN: 246608 AF XY: 0.0404

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.0215

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.0184

Gnomad FIN exome AF: 0.0547

Gnomad NFE exome AF: 0.0452

Gnomad OTH exome AF: 0.0377

GnomAD4 exome AF: 0.0428 AC: 62553 AN: 1460678 Hom.: 1432 Cov.: 32 AF XY: 0.0434 AC XY: 31549 AN XY: 726664

African (AFR) AF: 0.0120 AC: 403 AN: 33478

American (AMR) AF: 0.0224 AC: 1004 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 671 AN: 26136

East Asian (EAS) AF: 0.0221 AC: 877 AN: 39698

South Asian (SAS) AF: 0.0521 AC: 4495 AN: 86256

European-Finnish (FIN) AF: 0.0549 AC: 2871 AN: 52306

Middle Eastern (MID) AF: 0.0276 AC: 159 AN: 5768

European-Non Finnish (NFE) AF: 0.0448 AC: 49769 AN: 1111928

Other (OTH) AF: 0.0382 AC: 2304 AN: 60384

GnomAD4 genome AF: 0.0338 AC: 5152 AN: 152262 Hom.: 108 Cov.: 31 AF XY: 0.0347 AC XY: 2582 AN XY: 74442

African (AFR) AF: 0.0119 AC: 496 AN: 41536

American (AMR) AF: 0.0254 AC: 388 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3472

East Asian (EAS) AF: 0.0228 AC: 118 AN: 5182

South Asian (SAS) AF: 0.0552 AC: 266 AN: 4820

European-Finnish (FIN) AF: 0.0551 AC: 585 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0460 AC: 3128 AN: 68024

Other (OTH) AF: 0.0307 AC: 65 AN: 2114

Alfa AF: 0.0331 Hom.: 78

Bravo AF: 0.0291

TwinsUK AF: 0.0440 AC: 163

ALSPAC AF: 0.0376 AC: 145

ESP6500AA AF: 0.00960 AC: 29

ESP6500EA AF: 0.0425 AC: 230

ExAC AF: 0.0385 AC: 4554

Asia WGS AF: 0.0400 AC: 139 AN: 3478

EpiCase AF: 0.0427

EpiControl AF: 0.0431

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 20, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 9670930, 22610944, 25525159, 32113979, 16936732, 16518403)

Age related macular degeneration 14 Pathogenic:1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Complement component 2 deficiency Benign:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Complement component 2 deficiency;C3809653:Age related macular degeneration 14 Benign:1

Apr 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.35
PROVEAN	Benign	-0.59	N
REVEL	Uncertain	0.46
Sift	Benign	0.28	T
Sift4G	Benign	0.34	T
Polyphen		0.60	P
Vest4		0.30
MutPred		0.16		Loss of disorder (P = 0.1773)
MPC		0.92
ClinPred		0.032	T
GERP RS		-0.74
Varity_R		0.080
gMVP		0.46
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9332739; hg19: chr6-31903804; COSMIC: COSV54960858; COSMIC: COSV54960858;