chr1-56875054-C-A

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.277C>A(p.Gln93Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 1,612,406 control chromosomes in the GnomAD database, including 117,359 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8671 hom., cov: 32)

Exomes 𝑓: 0.38 ( 108688 hom. )

Consequence

C8A
NM_000562.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0330

Publications

29 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=2.7430058E-4).

BP6

Variant 1-56875054-C-A is Benign according to our data. Variant chr1-56875054-C-A is described in ClinVar as Benign. ClinVar VariationId is 17039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C8A	NM_000562.3 link	c.277C>A	p.Gln93Lys	missense_variant	Exon 3 of 11	ENST00000361249.4	NP_000553.1	P07357
C8A	XM_017002234.2 link	c.277C>A	p.Gln93Lys	missense_variant	Exon 3 of 8		XP_016857723.1
C8A	XM_011542079.3 link	c.277C>A	p.Gln93Lys	missense_variant	Exon 3 of 8		XP_011540381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C8A	ENST00000361249.4 link	c.277C>A	p.Gln93Lys	missense_variant	Exon 3 of 11	1	NM_000562.3	ENSP00000354458.3		P07357

Frequencies

GnomAD3 genomes

AF:

0.326

AC:

49463

AN:

151936

Hom.:

8678

Cov.:

show subpopulations

Gnomad AFR

AF:

0.210

Gnomad AMI

AF:

0.319

Gnomad AMR

AF:

0.249

Gnomad ASJ

AF:

0.404

Gnomad EAS

AF:

0.461

Gnomad SAS

AF:

0.503

Gnomad FIN

AF:

0.356

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.381

Gnomad OTH

AF:

0.338

GnomAD2 exomes

AF:

0.365

AC:

91400

AN:

250228

AF XY:

0.379

show subpopulations

Gnomad AFR exome

AF:

0.206

Gnomad AMR exome

AF:

0.211

Gnomad ASJ exome

AF:

0.410

Gnomad EAS exome

AF:

0.466

Gnomad FIN exome

AF:

0.352

Gnomad NFE exome

AF:

0.382

Gnomad OTH exome

AF:

0.362

GnomAD4 exome

AF:

0.381

AC:

556188

AN:

1460352

Hom.:

108688

Cov.:

AF XY:

0.386

AC XY:

280521

AN XY:

726472

show subpopulations

African (AFR)

AF:

0.205

AC:

6858

AN:

33452

American (AMR)

AF:

0.214

AC:

9546

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.405

AC:

10566

AN:

26104

East Asian (EAS)

AF:

0.419

AC:

16628

AN:

39660

South Asian (SAS)

AF:

0.503

AC:

43337

AN:

86206

European-Finnish (FIN)

AF:

0.351

AC:

18698

AN:

53346

Middle Eastern (MID)

AF:

0.450

AC:

2585

AN:

5740

European-Non Finnish (NFE)

AF:

0.383

AC:

425166

AN:

1110874

Other (OTH)

AF:

0.378

AC:

22804

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

18514

37028

55543

74057

92571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13290

26580

39870

53160

66450

<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:

0.325

AC:

49461

AN:

152054

Hom.:

8671

Cov.:

AF XY:

0.326

AC XY:

24256

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.210

AC:

8711

AN:

41496

American (AMR)

AF:

0.249

AC:

3803

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.404

AC:

1401

AN:

3464

East Asian (EAS)

AF:

0.460

AC:

2370

AN:

5154

South Asian (SAS)

AF:

0.503

AC:

2414

AN:

4798

European-Finnish (FIN)

AF:

0.356

AC:

3766

AN:

10566

Middle Eastern (MID)

AF:

0.395

AC:

116

AN:

294

European-Non Finnish (NFE)

AF:

0.381

AC:

25882

AN:

67986

Other (OTH)

AF:

0.336

AC:

709

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1696

3392

5089

6785

8481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

510

1020

1530

2040

2550

<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:

0.369

Hom.:

47784

Bravo

AF:

0.310

TwinsUK

AF:

0.394

AC:

1460

ALSPAC

AF:

0.384

AC:

1479

ESP6500AA

AF:

0.212

AC:

935

ESP6500EA

AF:

0.377

AC:

3239

ExAC

AF:

0.368

AC:

44637

Asia WGS

AF:

0.452

AC:

1575

AN:

3478

EpiCase

AF:

0.394

EpiControl

AF:

0.393

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2019

GeneDx

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, described by Zhang 1995 as complement component polymorphism -

COMPLEMENT COMPONENT 8, ALPHA SUBUNIT, A/B POLYMORPHISM

Benign:1

Sep 01, 1995

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Type I complement component 8 deficiency

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

7.5

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.011

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.37

MetaRNN

Benign

0.00027

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.26

PhyloP100

0.033

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.91

REVEL

Benign

0.099

Sift

Benign

0.64

Sift4G

Benign

0.83

Polyphen

0.048

Vest4

0.051

MPC

0.037

ClinPred

0.0023

GERP RS

3.4

Varity_R

0.37

gMVP

0.47

Mutation Taster

=98/2

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