Genetic Variant C2:c.-359-3248A>C (chr6-31924707-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000695637.1(C2):c.-359-3248A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0728 in 152,158 control chromosomes in the GnomAD database, including 518 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 0.073 ( 518 hom., cov: 32)

Consequence

C2
ENST00000695637.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.287

Publications

52 publications found

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 Gene-Disease associations (from GenCC):

complement component 2 deficiency
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

C2 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C2	NM_001178063.3 link	c.74-8903A>C		intron_variant	Intron 1 of 13		NP_001171534.1	P06681-2
C2	NM_001282457.2 link	c.-63-8903A>C		intron_variant	Intron 1 of 13		NP_001269386.1	B4DQI1Q53HP3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
C2	ENST00000695637.1 link	c.-359-3248A>C	intron_variant	Intron 1 of 17		ENSP00000512074.1	A0A8Q3WKN5
C2	ENST00000497706.6 link	c.-63-8903A>C	intron_variant	Intron 1 of 14	5	ENSP00000417482.2	E9PDZ0
C2	ENST00000452323.7 link	c.74-8903A>C	intron_variant	Intron 1 of 13	2	ENSP00000392322.2	P06681-2

Frequencies

GnomAD3 genomes

AF:

0.0729

AC:

11078

AN:

152040

Hom.:

518

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0516

Gnomad AMI

AF:

0.0714

Gnomad AMR

AF:

0.0335

Gnomad ASJ

AF:

0.0416

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0785

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.0554

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

GnomAD4 genome

AF:

0.0728

AC:

11077

AN:

152158

Hom.:

518

Cov.:

AF XY:

0.0676

AC XY:

5032

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0515

AC:

2138

AN:

41504

American (AMR)

AF:

0.0334

AC:

510

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0416

AC:

144

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0785

AC:

831

AN:

10586

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.107

AC:

7267

AN:

67984

Other (OTH)

AF:

0.0549

AC:

116

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

513

1026

1539

2052

2565

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0945

Hom.:

3490

Bravo

AF:

0.0689

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.0

(source)

DANN

Benign

0.73

PhyloP100

0.29

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over