6-31943161-G-T

Variant names:

• chr6-31943161-G-T
• rs547154
• NM_000063.6:c.1360+62G>T

Variant summary

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

The NM_000063.6(C2):​c.1360+62G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,612,262 control chromosomes in the GnomAD database, including 8,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as protective (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (1195 hom., cov: 31)
  • Exomes 𝑓: 0.098 (7801 hom.)
• Consequence: C2 NM_000063.6 intron
• Clinical Significance: protective no assertion criteria provided B:1
• Conservation: PhyloP100: -0.537
• Publications: 87 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)

ENSG00000244255 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2	NM_000063.6	MANE Select	c.1360+62G>T		intron	N/A	NP_000054.2
	C2	NM_001282458.2		c.1273+62G>T		intron	N/A	NP_001269387.1
	C2	NM_001145903.3		c.964+62G>T		intron	N/A	NP_001139375.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C2	ENST00000299367.10	TSL:1 MANE Select	c.1360+62G>T		intron	N/A	ENSP00000299367.5
	ENSG00000244255	ENST00000456570.5	TSL:2	c.901+62G>T		intron	N/A	ENSP00000410815.1
	C2	ENST00000695646.1		n.894G>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17723 AN: 151974 Hom.: 1197 Cov.: 31

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0571

Gnomad EAS AF: 0.0617

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.0568

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0908

Gnomad OTH AF: 0.131

GnomAD4 exome AF: 0.0982 AC: 143452 AN: 1460170 Hom.: 7801 Cov.: 33 AF XY: 0.0993 AC XY: 72139 AN XY: 726438

African (AFR) AF: 0.188 AC: 6306 AN: 33472

American (AMR) AF: 0.0738 AC: 3302 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0555 AC: 1451 AN: 26134

East Asian (EAS) AF: 0.0736 AC: 2922 AN: 39694

South Asian (SAS) AF: 0.156 AC: 13485 AN: 86246

European-Finnish (FIN) AF: 0.0651 AC: 3405 AN: 52290

Middle Eastern (MID) AF: 0.0713 AC: 411 AN: 5762

European-Non Finnish (NFE) AF: 0.0950 AC: 105567 AN: 1111488

Other (OTH) AF: 0.109 AC: 6603 AN: 60360

GnomAD4 genome AF: 0.117 AC: 17744 AN: 152092 Hom.: 1195 Cov.: 31 AF XY: 0.114 AC XY: 8509 AN XY: 74346

African (AFR) AF: 0.190 AC: 7876 AN: 41440

American (AMR) AF: 0.101 AC: 1542 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 198 AN: 3468

East Asian (EAS) AF: 0.0617 AC: 319 AN: 5172

South Asian (SAS) AF: 0.143 AC: 689 AN: 4828

European-Finnish (FIN) AF: 0.0568 AC: 602 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0908 AC: 6174 AN: 67984

Other (OTH) AF: 0.130 AC: 274 AN: 2106

Alfa AF: 0.102 Hom.: 1816

Bravo AF: 0.124

Asia WGS AF: 0.154 AC: 535 AN: 3478

ClinVar

Significance: protective

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Age related macular degeneration 14 Benign:1

May 18, 2015

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.70
DANN	Benign	0.76
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

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: rs547154; hg19: chr6-31910938; COSMIC: COSV54963335; COSMIC: COSV54963335;