1-56912476-G-T

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.1454G>T(p.Arg485Leu) 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 1,614,080 control chromosomes in the GnomAD database, including 4,764 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R485H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.10 ( 1238 hom., cov: 33)

Exomes 𝑓: 0.058 ( 3526 hom. )

Consequence

C8A
NM_000562.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.252

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=0.0047442913).

BP6

Variant 1-56912476-G-T is Benign according to our data. Variant chr1-56912476-G-T is described in ClinVar as Benign. ClinVar VariationId is 402461.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.1454G>T	p.Arg485Leu	missense_variant	Exon 10 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.1454G>T	p.Arg485Leu	missense_variant	Exon 10 of 11	1	NM_000562.3	ENSP00000354458.3

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15558

AN:

152120

Hom.:

1236

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:

0.0519

Gnomad SAS

AF:

0.138

Gnomad FIN

AF:

0.0470

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.0456

Gnomad OTH

AF:

0.104

GnomAD2 exomes

AF:

0.0755

AC:

18985

AN:

251300

AF XY:

0.0751

show subpopulations

Gnomad AFR exome

AF:

0.225

Gnomad AMR exome

AF:

0.0917

Gnomad ASJ exome

AF:

0.0454

Gnomad EAS exome

AF:

0.0518

Gnomad FIN exome

AF:

0.0483

Gnomad NFE exome

AF:

0.0454

Gnomad OTH exome

AF:

0.0711

GnomAD4 exome

AF:

0.0578

AC:

84527

AN:

1461842

Hom.:

3526

Cov.:

AF XY:

0.0596

AC XY:

43315

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.228

AC:

7623

AN:

33474

American (AMR)

AF:

0.0928

AC:

4149

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0430

AC:

1125

AN:

26136

East Asian (EAS)

AF:

0.0651

AC:

2583

AN:

39700

South Asian (SAS)

AF:

0.132

AC:

11411

AN:

86258

European-Finnish (FIN)

AF:

0.0459

AC:

2451

AN:

53414

Middle Eastern (MID)

AF:

0.112

AC:

646

AN:

5766

European-Non Finnish (NFE)

AF:

0.0454

AC:

50445

AN:

1111976

Other (OTH)

AF:

0.0678

AC:

4094

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

4874

9748

14621

19495

24369

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:

15580

AN:

152238

Hom.:

1238

Cov.:

AF XY:

0.102

AC XY:

7590

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.216

AC:

8948

AN:

41502

American (AMR)

AF:

0.108

AC:

1655

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0415

AC:

144

AN:

3472

East Asian (EAS)

AF:

0.0518

AC:

268

AN:

5174

South Asian (SAS)

AF:

0.138

AC:

668

AN:

4826

European-Finnish (FIN)

AF:

0.0470

AC:

499

AN:

10622

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0456

AC:

3104

AN:

68028

Other (OTH)

AF:

0.102

AC:

216

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

679

1358

2038

2717

3396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<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:

0.0350

Hom.:

Bravo

AF:

0.110

TwinsUK

AF:

0.0467

AC:

173

ALSPAC

AF:

0.0418

AC:

161

ESP6500AA

AF:

0.196

AC:

864

ESP6500EA

AF:

0.0430

AC:

370

ExAC

AF:

0.0774

AC:

9394

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

Jan 29, 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

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.90

MutationAssessor

Pathogenic

2.9

PhyloP100

0.25

PrimateAI

Benign

0.20

PROVEAN

Pathogenic

-5.5

REVEL

Uncertain

0.34

Sift

Uncertain

0.0090

Sift4G

Benign

0.10

Vest4

0.11

ClinPred

0.088

GERP RS

0.70

Varity_R

0.66

gMVP

0.78

Mutation Taster

=92/8

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