6-31936027-G-C

Position:

chr6-31936027-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 108 hom., cov: 31)

Exomes 𝑓: 0.043 ( 1432 hom. )

Consequence

C2
NM_000063.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:11

Conservation

PhyloP100: 0.346

Variant links:

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]

C2 links:

ENSG00000244255 (HGNC:):

ENSG00000244255 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 12130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31936027-G-C is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C2	NM_000063.6 linkuse as main transcript	c.954G>C	p.Glu318Asp	missense_variant	7/18	ENST00000299367.10	NP_000054.2	P06681-1Q5JP69Q53HP3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C2	ENST00000299367.10 linkuse as main transcript	c.954G>C	p.Glu318Asp	missense_variant	7/18	1	NM_000063.6	ENSP00000299367.5		P06681-1
ENSG00000244255	ENST00000456570.5 linkuse as main transcript	c.530-1292G>C		intron_variant		2		ENSP00000410815.1		B4E1Z4

Frequencies

GnomAD3 genomes

AF:

0.0338

AC:

5147

AN:

152144

Hom.:

107

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0386

AC:

9529

AN:

246608

Hom.:

221

AF XY:

0.0404

AC XY:

5432

AN XY:

134420

show subpopulations

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 SAS exome

AF:

0.0532

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.:

AF XY:

0.0434

AC XY:

31549

AN XY:

726664

show subpopulations

Gnomad4 AFR exome

AF:

0.0120

Gnomad4 AMR exome

AF:

0.0224

Gnomad4 ASJ exome

AF:

0.0257

Gnomad4 EAS exome

AF:

0.0221

Gnomad4 SAS exome

AF:

0.0521

Gnomad4 FIN exome

AF:

0.0549

Gnomad4 NFE exome

AF:

0.0448

Gnomad4 OTH exome

AF:

0.0382

GnomAD4 genome

AF:

0.0338

AC:

5152

AN:

152262

Hom.:

108

Cov.:

AF XY:

0.0347

AC XY:

2582

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0119

Gnomad4 AMR

AF:

0.0254

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.0228

Gnomad4 SAS

AF:

0.0552

Gnomad4 FIN

AF:

0.0551

Gnomad4 NFE

AF:

0.0460

Gnomad4 OTH

AF:

0.0307

Alfa

AF:

0.0331

Hom.:

Bravo

AF:

0.0291

TwinsUK

AF:

0.0440

AC:

163

ALSPAC

AF:

0.0376

AC:

145

ESP6500AA

AF:

0.00960

AC:

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:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2020	This variant is associated with the following publications: (PMID: 9670930, 22610944, 25525159, 32113979, 16936732, 16518403) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Age related macular degeneration 14

Pathogenic:1Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2006	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Complement component 2 deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.056

T;.;T;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.62

T;T;T;T

MetaRNN

Benign

0.0063

T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.8

.;.;L;.

PROVEAN

Benign

-0.59

N;N;N;N

REVEL

Uncertain

0.46

Sift

Benign

0.28

T;T;T;T

Sift4G

Benign

0.34

T;T;T;T

Polyphen

0.60

P;P;B;.

Vest4

0.30

MutPred

0.16

.;.;Loss of disorder (P = 0.1773);.;

MPC

0.92

ClinPred

0.032

GERP RS

-0.74

Varity_R

0.080

gMVP

0.46

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over