6-31916180-A-G

Variant names:

• chr6-31916180-A-G
• rs644045
• ENST00000695637.1:c.-359-11775A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000695637.1(C2):​c.-359-11775A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 151,964 control chromosomes in the GnomAD database, including 40,673 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.73 (40673 hom., cov: 31)
• Consequence: C2 ENST00000695637.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.86
• Publications: 46 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]

C2 Gene-Disease associations (from GenCC):

• complement component 2 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2	NM_001178063.3	c.73+15041A>G		intron_variant	Intron 1 of 13		NP_001171534.1
C2	NM_001282457.2	c.-63-17430A>G		intron_variant	Intron 1 of 13		NP_001269386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C2	ENST00000695637.1	c.-359-11775A>G		intron_variant	Intron 1 of 17			ENSP00000512074.1
C2	ENST00000497706.6	c.-63-17430A>G		intron_variant	Intron 1 of 14	5		ENSP00000417482.2
C2	ENST00000452323.7	c.73+15041A>G		intron_variant	Intron 1 of 13	2		ENSP00000392322.2

Frequencies

GnomAD3 genomes AF: 0.726 AC: 110274 AN: 151846 Hom.: 40617 Cov.: 31

Gnomad AFR AF: 0.791

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.846

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.653

Gnomad OTH AF: 0.770

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.726 AC: 110385 AN: 151964 Hom.: 40673 Cov.: 31 AF XY: 0.731 AC XY: 54263 AN XY: 74238

African (AFR) AF: 0.791 AC: 32793 AN: 41434

American (AMR) AF: 0.811 AC: 12376 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 3047 AN: 3470

East Asian (EAS) AF: 0.803 AC: 4154 AN: 5172

South Asian (SAS) AF: 0.845 AC: 4071 AN: 4818

European-Finnish (FIN) AF: 0.658 AC: 6919 AN: 10522

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.653 AC: 44408 AN: 67972

Other (OTH) AF: 0.772 AC: 1631 AN: 2112

Alfa AF: 0.687 Hom.: 131313

Bravo AF: 0.741

Asia WGS AF: 0.882 AC: 3069 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.18
DANN	Benign	0.43
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs644045; hg19: chr6-31883957; COSMIC: COSV68663726; COSMIC: COSV68663726;