rs1042663

Variant names:

• chr6-31937353-G-A
• rs1042663
• NM_000063.6:c.1023G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000063.6(C2):​c.1023G>A​(p.Ala341Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0996 in 1,612,312 control chromosomes in the GnomAD database, including 8,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1220 hom., cov: 29)
  • Exomes 𝑓: 0.098 (7765 hom.)
• Consequence: C2 NM_000063.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0410
• Publications: 37 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.011).
• BP6: Variant 6-31937353-G-A is Benign according to our data. Variant chr6-31937353-G-A is described in ClinVar as Benign. ClinVar VariationId is 356245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.041 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

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.1023G>A	p.Ala341Ala	synonymous	Exon 8 of 18	NP_000054.2
	C2	NM_001282458.2		c.936G>A	p.Ala312Ala	synonymous	Exon 8 of 18	NP_001269387.1	A0A0G2JL69
	C2	NM_001145903.3		c.627G>A	p.Ala209Ala	synonymous	Exon 6 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.1023G>A	p.Ala341Ala	synonymous	Exon 8 of 18	ENSP00000299367.5	P06681-1
	ENSG00000244255	ENST00000456570.5	TSL:2	c.564G>A	p.Ala188Ala	synonymous	Exon 5 of 30	ENSP00000410815.1	B4E1Z4
	ENSG00000244255	ENST00000477310.1	TSL:5	c.477G>A	p.Ala159Ala	synonymous	Exon 4 of 28	ENSP00000418996.1	E7ETN3

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17727 AN: 151746 Hom.: 1222 Cov.: 29

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0574

Gnomad EAS AF: 0.0589

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0577

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0908

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.0969 AC: 23910 AN: 246640 AF XY: 0.0999

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.0704

Gnomad ASJ exome AF: 0.0522

Gnomad EAS exome AF: 0.0591

Gnomad FIN exome AF: 0.0636

Gnomad NFE exome AF: 0.0908

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0978 AC: 142895 AN: 1460448 Hom.: 7765 Cov.: 33 AF XY: 0.0989 AC XY: 71870 AN XY: 726556

African (AFR) AF: 0.188 AC: 6303 AN: 33470

American (AMR) AF: 0.0739 AC: 3305 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0555 AC: 1450 AN: 26132

East Asian (EAS) AF: 0.0713 AC: 2832 AN: 39698

South Asian (SAS) AF: 0.156 AC: 13443 AN: 86258

European-Finnish (FIN) AF: 0.0651 AC: 3403 AN: 52304

Middle Eastern (MID) AF: 0.0716 AC: 413 AN: 5768

European-Non Finnish (NFE) AF: 0.0946 AC: 105160 AN: 1111724

Other (OTH) AF: 0.109 AC: 6586 AN: 60370

GnomAD4 genome AF: 0.117 AC: 17747 AN: 151864 Hom.: 1220 Cov.: 29 AF XY: 0.115 AC XY: 8509 AN XY: 74238

African (AFR) AF: 0.191 AC: 7911 AN: 41358

American (AMR) AF: 0.100 AC: 1534 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0574 AC: 199 AN: 3468

East Asian (EAS) AF: 0.0589 AC: 302 AN: 5130

South Asian (SAS) AF: 0.141 AC: 674 AN: 4790

European-Finnish (FIN) AF: 0.0577 AC: 610 AN: 10580

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0908 AC: 6173 AN: 67962

Other (OTH) AF: 0.130 AC: 274 AN: 2108

Alfa AF: 0.0989 Hom.: 3108

Bravo AF: 0.123

Asia WGS AF: 0.155 AC: 536 AN: 3478

EpiCase AF: 0.0869

EpiControl AF: 0.0884

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Age related macular degeneration 14 (1)
-	-	1	Complement component 2 deficiency (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.5
DANN	Benign	0.41
PhyloP100		-0.041
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1042663; hg19: chr6-31905130;