chr6-31902549-G-A

Variant names:

• chr6-31902549-G-A
• rs558702
• ENST00000695637.1:c.-360+4274G>A

Variant summary

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

The ENST00000695637.1(C2):​c.-360+4274G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0747 in 152,338 control chromosomes in the GnomAD database, including 536 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 0.075 (536 hom., cov: 31)
• Consequence: C2 ENST00000695637.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.559
• Publications: 65 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2	NM_001178063.3	c.73+1410G>A		intron_variant	Intron 1 of 13		NP_001171534.1
C2	NM_001282457.2	c.-64+4607G>A		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.-360+4274G>A		intron_variant	Intron 1 of 17			ENSP00000512074.1
C2	ENST00000497706.6	c.-64+4607G>A		intron_variant	Intron 1 of 14	5		ENSP00000417482.2
C2	ENST00000452323.7	c.73+1410G>A		intron_variant	Intron 1 of 13	2		ENSP00000392322.2

Frequencies

GnomAD3 genomes AF: 0.0747 AC: 11378 AN: 152222 Hom.: 536 Cov.: 31

Gnomad AFR AF: 0.0583

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0342

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0793

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.0564

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

GnomAD4 genome AF: 0.0747 AC: 11382 AN: 152338 Hom.: 536 Cov.: 31 AF XY: 0.0693 AC XY: 5160 AN XY: 74484

African (AFR) AF: 0.0583 AC: 2424 AN: 41590

American (AMR) AF: 0.0341 AC: 522 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 133 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0793 AC: 842 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7272 AN: 68004

Other (OTH) AF: 0.0558 AC: 118 AN: 2116

Alfa AF: 0.0983 Hom.: 3629

Bravo AF: 0.0709

Asia WGS AF: 0.00751 AC: 27 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.7
DANN	Benign	0.68
PhyloP100		-0.56
PromoterAI		-0.056	Neutral
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: rs558702; hg19: chr6-31870326;