NM_000063.6:c.1360+62G>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: 91 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

Classification was made for transcript:

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

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		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	Intron 10 of 17	Prot: NP_000054.2
	C2 NM_001282458.2		c.1273+62G>T	intron	Intron 10 of 17	Prot: NP_001269387.1 UniProt:
	C2 NM_001145903.3		c.964+62G>T	intron	Intron 8 of 15	Prot: NP_001139375.1 UniProt:

C2 NM_000063.6

MANE Select

HGVSc / HGVSpc.1360+62G>T

Exon rankIntron 10 of 17

intron

Prot: NP_000054.2

C2 NM_001282458.2

HGVSc / HGVSpc.1273+62G>T

Exon rankIntron 10 of 17

intron

Prot: NP_001269387.1UniProt: A0A0G2JL69

C2 NM_001145903.3

HGVSc / HGVSpc.964+62G>T

Exon rankIntron 8 of 15

intron

Prot: NP_001139375.1UniProt: P06681-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	C2 ENST00000299367.10	TSL:1MANE Select	c.1360+62G>T	intron	Intron 10 of 17	Prot: ENSP00000299367.5 UniProt:
	ENSG00000244255 ENST00000456570.5	TSL:2	c.901+62G>T	intron	Intron 7 of 29	Prot: ENSP00000410815.1 UniProt:
	ENSG00000244255 ENST00000477310.1	TSL:5	c.674-64G>T	intron	Intron 5 of 27	Prot: ENSP00000418996.1 UniProt:

C2 ENST00000299367.10

TSL:1MANE Select

HGVSc / HGVSpc.1360+62G>T

Exon rankIntron 10 of 17

intron

Prot: ENSP00000299367.5UniProt: P06681-1

ENSG00000244255 ENST00000456570.5

TSL:2

HGVSc / HGVSpc.901+62G>T

Exon rankIntron 7 of 29

intron

Prot: ENSP00000410815.1UniProt: K9J7H5

ENSG00000244255 ENST00000477310.1

TSL:5

HGVSc / HGVSpc.674-64G>T

Exon rankIntron 5 of 27

intron

Prot: ENSP00000418996.1UniProt: 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	AF: 0.117	AC:17723	Hom:1197	AN:151974	Cov:31
GnomAD4 exome	AF: 0.0982	AC:143452	Hom:7801	AN:1460170	Cov:33
GnomAD4 genome	AF: 0.117	AC:17744	Hom:1195	AN:152092	Cov:31
TOPMed (Bravo)	AF: 0.124	AC:32723	Hom:2411	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.104	AC:33286	Hom:1976	AN:321076	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.120	AC:282	Hom:23	AN:2342	Cov:
GenomeAsia100K	AF: 0.154	AC:535	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0830	AC:604	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.114	AC:20	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0956	AC:11718	Hom:549	AN:122554	Cov:
Turkish Variome	AF: 0.0750	AC:116	Hom:6	AN:1546	Cov:
UK10K	AF: 0.0972	AC:735	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0588	AC:527	Hom:11	AN:8960	Cov:

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 pred.	Score	Prediction
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	100/0	polymorphism (auto)
PhyloP100	Benign	-0.54

Showing 8 of 8 scores

Splicing Scores

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

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

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