Genetic Variant NM_000063.6:c.876C>A (chr6-31935949-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000063.6(C2):c.876C>A(p.Ser292Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S292S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

C2
NM_000063.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.15

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2543814).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C2	NM_000063.6	MANE Select	c.876C>A	p.Ser292Arg	missense	Exon 7 of 18	NP_000054.2
C2	NM_001282458.2		c.789C>A	p.Ser263Arg	missense	Exon 7 of 18	NP_001269387.1	A0A0G2JL69
C2	NM_001145903.3		c.480C>A	p.Ser160Arg	missense	Exon 5 of 16	NP_001139375.1	P06681-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C2	ENST00000299367.10	TSL:1 MANE Select	c.876C>A	p.Ser292Arg	missense	Exon 7 of 18	ENSP00000299367.5	P06681-1
ENSG00000244255	ENST00000456570.5	TSL:2	c.530-1370C>A		intron	N/A	ENSP00000410815.1	B4E1Z4
C2	ENST00000447952.7	TSL:3	c.690C>A	p.Ser230Arg	missense	Exon 6 of 17	ENSP00000391354.3	F2Z3N2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Benign

-0.28

CADD

Benign

0.23

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.046

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.2

PhyloP100

-3.2

PROVEAN

Benign

0.27

REVEL

Uncertain

0.43

Sift

Benign

1.0

Sift4G

Benign

0.70

Polyphen

1.0

Vest4

0.27

MutPred

0.65

Gain of catalytic residue at S292 (P = 0.0682)

MVP

0.73

MPC

1.0

ClinPred

0.42

GERP RS

-8.8

Varity_R

0.31

gMVP

0.50

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over