rs9267665

Variant names:

• chr6-31903079-C-T
• rs9267665
• ENST00000695637.1:c.-360+4804C>T

Variant summary

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

The NM_001178063.3(C2):​c.73+1940C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0723 in 152,148 control chromosomes in the GnomAD database, including 616 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 0.072 (616 hom., cov: 31)
• Consequence: C2 NM_001178063.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 40 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 (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2	NM_001178063.3	c.73+1940C>T		intron_variant	Intron 1 of 13		NP_001171534.1
C2	NM_001282457.2	c.-64+5137C>T		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+4804C>T		intron_variant	Intron 1 of 17			ENSP00000512074.1
C2	ENST00000497706.6	c.-64+5137C>T		intron_variant	Intron 1 of 14	5		ENSP00000417482.2
C2	ENST00000452323.7	c.73+1940C>T		intron_variant	Intron 1 of 13	2		ENSP00000392322.2

Frequencies

GnomAD3 genomes AF: 0.0723 AC: 10998 AN: 152030 Hom.: 617 Cov.: 31

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0825

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.0508

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0360

Gnomad OTH AF: 0.0994

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

GnomAD4 genome AF: 0.0723 AC: 11006 AN: 152148 Hom.: 616 Cov.: 31 AF XY: 0.0711 AC XY: 5290 AN XY: 74408

African (AFR) AF: 0.141 AC: 5834 AN: 41460

American (AMR) AF: 0.0824 AC: 1260 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 406 AN: 3468

East Asian (EAS) AF: 0.0513 AC: 265 AN: 5170

South Asian (SAS) AF: 0.103 AC: 496 AN: 4818

European-Finnish (FIN) AF: 0.00508 AC: 54 AN: 10624

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0360 AC: 2447 AN: 68008

Other (OTH) AF: 0.0984 AC: 208 AN: 2114

Alfa AF: 0.0494 Hom.: 755

Bravo AF: 0.0799

Asia WGS AF: 0.0690 AC: 240 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	0.32
DANN	Benign	0.65
PhyloP100		-2.0
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: rs9267665; hg19: chr6-31870856;