1-56917642-G-C

Variant names:

• chr1-56917642-G-C
• rs1342440
• NM_000562.3:c.1681G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 in silico tools predict 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 Likely benign in UniProt. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.989

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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	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	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.: 33

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

GnomAD3 exomes AF: 0.0755 AC: 18974 AN: 251252 Hom.: 1063 AF XY: 0.0751 AC XY: 10198 AN XY: 135788

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 SAS exome AF: 0.134

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.: 31 AF XY: 0.0595 AC XY: 43306 AN XY: 727234

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.0927

Gnomad4 ASJ exome AF: 0.0430

Gnomad4 EAS exome AF: 0.0650

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.0459

Gnomad4 NFE exome AF: 0.0454

Gnomad4 OTH exome AF: 0.0678

GnomAD4 genome AF: 0.102 AC: 15600 AN: 152278 Hom.: 1252 Cov.: 33 AF XY: 0.102 AC XY: 7595 AN XY: 74464

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.0415

Gnomad4 EAS AF: 0.0519

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.0471

Gnomad4 NFE AF: 0.0457

Gnomad4 OTH AF: 0.103

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

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.56	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.023
Sift	Benign	0.55	T
Sift4G	Benign	0.76	T
Polyphen		0.063	B
Vest4		0.017
MPC		0.034
ClinPred		0.0062	T
GERP RS		2.7
Varity_R		0.11
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs1342440; hg19: chr1-57383315; COSMIC: COSV63484457;