1-56917642-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000562.3(C8A):c.1681G>C(p.Glu561Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.062 in 1,614,138 control chromosomes in the GnomAD database, including 4,774 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E561E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.10 ( 1252 hom., cov: 33)

Exomes 𝑓: 0.058 ( 3522 hom. )

Consequence

C8A
NM_000562.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.989

Publications

19 publications found

Variant links:

Genes affected

C8A (HGNC:1352): (complement C8 alpha chain) C8 is a component of the complement system and contains three polypeptides, alpha, beta and gamma. This gene encodes the alpha subunit of C8. C8 participates in the formation of the membrane attack complex (MAC). The MAC assembles on bacterial membranes to form a pore, permitting disruption of bacterial membrane organization. Mutations in this gene cause complement C8 alpha-gamma deficiency. [provided by RefSeq, Nov 2008]

C8A Gene-Disease associations (from GenCC):

type I complement component 8 deficiency
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

C8A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046334267).

BP6

Variant 1-56917642-G-C is Benign according to our data. Variant chr1-56917642-G-C is described in ClinVar as Benign. ClinVar VariationId is 402464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C8A	NM_000562.3 link	c.1681G>C	p.Glu561Gln	missense_variant	Exon 11 of 11	ENST00000361249.4	NP_000553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C8A	ENST00000361249.4 link	c.1681G>C	p.Glu561Gln	missense_variant	Exon 11 of 11	1	NM_000562.3	ENSP00000354458.3

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15578

AN:

152160

Hom.:

1250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.216

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.0415

Gnomad EAS

AF:

0.0520

Gnomad SAS

AF:

0.138

Gnomad FIN

AF:

0.0471

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.0457

Gnomad OTH

AF:

0.104

GnomAD2 exomes

AF:

0.0755

AC:

18974

AN:

251252

AF XY:

0.0751

show subpopulations

Gnomad AFR exome

AF:

0.224

Gnomad AMR exome

AF:

0.0916

Gnomad ASJ exome

AF:

0.0454

Gnomad EAS exome

AF:

0.0517

Gnomad FIN exome

AF:

0.0483

Gnomad NFE exome

AF:

0.0454

Gnomad OTH exome

AF:

0.0711

GnomAD4 exome

AF:

0.0578

AC:

84516

AN:

1461860

Hom.:

3522

Cov.:

AF XY:

0.0595

AC XY:

43306

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.227

AC:

7616

AN:

33478

American (AMR)

AF:

0.0927

AC:

4146

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0430

AC:

1125

AN:

26136

East Asian (EAS)

AF:

0.0650

AC:

2579

AN:

39698

South Asian (SAS)

AF:

0.132

AC:

11423

AN:

86256

European-Finnish (FIN)

AF:

0.0459

AC:

2451

AN:

53420

Middle Eastern (MID)

AF:

0.112

AC:

645

AN:

5762

European-Non Finnish (NFE)

AF:

0.0454

AC:

50436

AN:

1111990

Other (OTH)

AF:

0.0678

AC:

4095

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

4248

8496

12743

16991

21239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2080

4160

6240

8320

10400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.102

AC:

15600

AN:

152278

Hom.:

1252

Cov.:

AF XY:

0.102

AC XY:

7595

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.216

AC:

8961

AN:

41532

American (AMR)

AF:

0.108

AC:

1659

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0415

AC:

144

AN:

3472

East Asian (EAS)

AF:

0.0519

AC:

268

AN:

5166

South Asian (SAS)

AF:

0.138

AC:

666

AN:

4822

European-Finnish (FIN)

AF:

0.0471

AC:

500

AN:

10626

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0457

AC:

3107

AN:

68034

Other (OTH)

AF:

0.103

AC:

217

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

653

1305

1958

2610

3263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<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:

0.0530

Hom.:

240

Bravo

AF:

0.110

TwinsUK

AF:

0.0485

AC:

180

ALSPAC

AF:

0.0431

AC:

166

ESP6500AA

AF:

0.205

AC:

903

ESP6500EA

AF:

0.0473

AC:

407

ExAC

AF:

0.0774

AC:

9393

Asia WGS

AF:

0.107

AC:

373

AN:

3478

EpiCase

AF:

0.0478

EpiControl

AF:

0.0510

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.018

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0046

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.56

PhyloP100

0.99

PrimateAI

Benign

0.24

PROVEAN

Benign

0.33

REVEL

Benign

0.023

Sift

Benign

0.55

Sift4G

Benign

0.76

Polyphen

0.063

Vest4

0.017

MPC

0.034

ClinPred

0.0062

GERP RS

2.7

Varity_R

0.11

gMVP

0.50

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over