chr6-31943161-G-T

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

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 cumulative frequency of 0.1 (AC=161,196) in the gnomAD database across 1,612,262 control chromosomes, including 8,996 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.187. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000244255 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

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

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
• BA1: GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1865 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000063.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	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	A0A0G2JL69
	C2	NM_001145903.3		c.964+62G>T		intron	N/A	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.1360+62G>T		intron	N/A	ENSP00000299367.5	P06681-1
	ENSG00000244255	ENST00000456570.5	TSL:2	c.901+62G>T		intron	N/A	ENSP00000410815.1	K9J7H5
	ENSG00000244255	ENST00000477310.1	TSL:5	c.674-64G>T		intron	N/A	ENSP00000418996.1	E7ETN3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	0.117	17723	1197	151974	31
GnomAD4 exome	0.0982	143452	7801	1460170	33
GnomAD4 genome	0.117	17744	1195	152092	31
TOPMed (Bravo)	0.124	32723	2411	264690
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.104	33286	1976	321076
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	0.120	282	23	2342
GenomeAsia100K	0.154	535		3478
Korea4K (4,157 Koreans)	0.0830	604		7234
Qatari Genome	0.114	20		176
ToMMo 61KJPN (+60KJPN MNV)	0.0956	11718	549	122554
Turkish Variome	0.0750	116	6	1546
UK10K	0.0972	735		7562
WBBC (Westlake BioBank for Chinese) pilot	0.0588	527	11	8960

Showing 13 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0777	5655	72748	0.0715	7759	108452

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: protective

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Age related macular degeneration 14 (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Benign	-	4.2
BayesDel_noAF	Benign	-	-0.85
CADD	Benign	-	0.70
DANN	Benign	-	0.76
GPN-Star LLR	N/A	-	-1.3
GPN-Star score	N/A	-	1.3
Mutation Taster	N/A	polymorphism (auto)	100/0
PhyloP100	Benign	-	-0.54

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs547154;

hg19: chr6-31910938;

COSMIC: COSV54963335;

COSMIC: COSV54963335;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar