6-31936004-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000063.6(C2):c.931G>A(p.Asp311Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

C2
NM_000063.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.630

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:

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

C2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2729483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2	NM_000063.6 link	c.931G>A	p.Asp311Asn	missense_variant	Exon 7 of 18	ENST00000299367.10	NP_000054.2	P06681-1Q5JP69Q53HP3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2	ENST00000299367.10 link	c.931G>A	p.Asp311Asn	missense_variant	Exon 7 of 18	1	NM_000063.6	ENSP00000299367.5		P06681-1
ENSG00000244255	ENST00000456570.5 link	c.530-1315G>A		intron_variant	Intron 4 of 29	2		ENSP00000410815.1		B4E1Z4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000811

AC:

AN:

246648

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134440

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460756

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726694

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000169

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 311 of the C2 protein (p.Asp311Asn). This variant is present in population databases (rs774981560, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with C2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1512092). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.10

T;.;T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

.;.;M;.

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.084

T;D;D;T

Sift4G

Benign

0.36

T;T;T;T

Polyphen

0.73

P;P;B;.

Vest4

0.20

MutPred

0.49

.;.;Gain of sheet (P = 0.1945);.;

MVP

0.76

MPC

0.59

ClinPred

0.15

GERP RS

1.4

Varity_R

0.12

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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