6-31936003-C-A

Variant names:

• chr6-31936003-C-A
• rs146165915
• NM_000063.6:c.930C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000063.6(C2):​c.930C>A​(p.Asn310Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N310S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: C2 NM_000063.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.33
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21272916).

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.930C>A	p.Asn310Lys	missense	Exon 7 of 18	NP_000054.2
	C2	NM_001282458.2		c.843C>A	p.Asn281Lys	missense	Exon 7 of 18	NP_001269387.1	A0A0G2JL69
	C2	NM_001145903.3		c.534C>A	p.Asn178Lys	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.930C>A	p.Asn310Lys	missense	Exon 7 of 18	ENSP00000299367.5	P06681-1
	ENSG00000244255	ENST00000456570.5	TSL:2	c.530-1316C>A		intron	N/A	ENSP00000410815.1	B4E1Z4
	C2	ENST00000447952.7	TSL:3	c.744C>A	p.Asn248Lys	missense	Exon 6 of 17	ENSP00000391354.3	F2Z3N2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460750 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726690

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: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52312

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

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

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.0010
DANN	Benign	0.74
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.83	L
PhyloP100		-4.3
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.29
Sift	Benign	0.078	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.073
MutPred		0.58		Gain of ubiquitination at N310 (P = 0.0146)
MVP		0.35
MPC		0.35
ClinPred		0.093	T
GERP RS		-12
Varity_R		0.10
gMVP		0.22
Mutation Taster		=94/6	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: rs146165915; hg19: chr6-31903780;