6-31936013-C-T

Variant names:

• chr6-31936013-C-T
• rs1206018325
• NM_000063.6:c.940C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000063.6(C2):​c.940C>T​(p.Arg314Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R314G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: C2 NM_000063.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.692
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2	NM_000063.6	MANE Select	c.940C>T	p.Arg314Trp	missense	Exon 7 of 18	NP_000054.2
	C2	NM_001282458.2		c.853C>T	p.Arg285Trp	missense	Exon 7 of 18	NP_001269387.1	A0A0G2JL69
	C2	NM_001145903.3		c.544C>T	p.Arg182Trp	missense	Exon 5 of 16	NP_001139375.1	P06681-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2	ENST00000299367.10	TSL:1 MANE Select	c.940C>T	p.Arg314Trp	missense	Exon 7 of 18	ENSP00000299367.5	P06681-1
	ENSG00000244255	ENST00000456570.5	TSL:2	c.530-1306C>T		intron	N/A	ENSP00000410815.1	B4E1Z4
	C2	ENST00000447952.7	TSL:3	c.754C>T	p.Arg252Trp	missense	Exon 6 of 17	ENSP00000391354.3	F2Z3N2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246640 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460764 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726698

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000540 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.089	N
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.69
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.19
MutPred		0.62		Loss of disorder (P = 0.0076)
MVP		0.86
MPC		0.34
ClinPred		0.65	D
GERP RS		0.24
Varity_R		0.23
gMVP		0.46
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs1206018325; hg19: chr6-31903790;