6-31944232-G-C

Position:

chr6-31944232-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000063.6(C2):c.1902+6G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 1,595,440 control chromosomes in the GnomAD database, including 2,913 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.048 ( 282 hom., cov: 31)

Exomes 𝑓: 0.050 ( 2631 hom. )

Consequence

C2
NM_000063.6 splice_region, intron

Scores

Splicing: ADA: 0.0006264

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.00800

Variant links:

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 links:

ENSG00000244255 (HGNC:):

ENSG00000244255 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 6-31944232-G-C is Benign according to our data. Variant chr6-31944232-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 356256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31944232-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C2	NM_000063.6 linkuse as main transcript	c.1902+6G>C		splice_region_variant, intron_variant		ENST00000299367.10	NP_000054.2	P06681-1Q5JP69Q53HP3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C2	ENST00000299367.10 linkuse as main transcript	c.1902+6G>C		splice_region_variant, intron_variant		1	NM_000063.6	ENSP00000299367.5		P06681-1
ENSG00000244255	ENST00000456570.5 linkuse as main transcript	c.1443+6G>C		splice_region_variant, intron_variant		2		ENSP00000410815.1		B4E1Z4

Frequencies

GnomAD3 genomes

AF:

0.0482

AC:

7333

AN:

152050

Hom.:

282

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0266

Gnomad AMI

AF:

0.0857

Gnomad AMR

AF:

0.0306

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00926

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0488

Gnomad OTH

AF:

0.0416

GnomAD3 exomes

AF:

0.0561

AC:

13833

AN:

246480

Hom.:

677

AF XY:

0.0621

AC XY:

8350

AN XY:

134368

show subpopulations

Gnomad AFR exome

AF:

0.0275

Gnomad AMR exome

AF:

0.0214

Gnomad ASJ exome

AF:

0.00903

Gnomad EAS exome

AF:

0.00482

Gnomad SAS exome

AF:

0.121

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.0487

Gnomad OTH exome

AF:

0.0490

GnomAD4 exome

AF:

0.0497

AC:

71680

AN:

1443272

Hom.:

2631

Cov.:

AF XY:

0.0528

AC XY:

37973

AN XY:

719252

show subpopulations

Gnomad4 AFR exome

AF:

0.0241

Gnomad4 AMR exome

AF:

0.0221

Gnomad4 ASJ exome

AF:

0.00968

Gnomad4 EAS exome

AF:

0.00308

Gnomad4 SAS exome

AF:

0.118

Gnomad4 FIN exome

AF:

0.140

Gnomad4 NFE exome

AF:

0.0449

Gnomad4 OTH exome

AF:

0.0401

GnomAD4 genome

AF:

0.0482

AC:

7335

AN:

152168

Hom.:

282

Cov.:

AF XY:

0.0531

AC XY:

3953

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0266

Gnomad4 AMR

AF:

0.0306

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00908

Gnomad4 SAS

AF:

0.111

Gnomad4 FIN

AF:

0.156

Gnomad4 NFE

AF:

0.0488

Gnomad4 OTH

AF:

0.0407

Alfa

AF:

0.0422

Hom.:

Bravo

AF:

0.0360

Asia WGS

AF:

0.0360

AC:

123

AN:

3478

EpiCase

AF:

0.0469

EpiControl

AF:

0.0459

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Age related macular degeneration 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Complement component 2 deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Atypical hemolytic-uremic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Macular degeneration

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00063

dbscSNV1_RF

Benign

0.10

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over