rs652785

chr1-56875054-C-A

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.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. 14/19 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0330

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=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 id is 17039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-56875054-C-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
C8A	NM_000562.3	c.277C>A	p.Gln93Lys	missense_variant	3/11	ENST00000361249.4
C8A	XM_017002234.2	c.277C>A	p.Gln93Lys	missense_variant	3/8
C8A	XM_011542079.3	c.277C>A	p.Gln93Lys	missense_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C8A	ENST00000361249.4	c.277C>A	p.Gln93Lys	missense_variant	3/11	1	NM_000562.3	P4

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49463 AN: 151936 Hom.: 8678 Cov.: 32

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

GnomAD3 exomes AF: 0.365 AC: 91400 AN: 250228 Hom.: 17867 AF XY: 0.379 AC XY: 51316 AN XY: 135222

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 SAS exome AF: 0.498

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.: 39 AF XY: 0.386 AC XY: 280521 AN XY: 726472

Gnomad4 AFR exome AF: 0.205

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.405

Gnomad4 EAS exome AF: 0.419

Gnomad4 SAS exome AF: 0.503

Gnomad4 FIN exome AF: 0.351

Gnomad4 NFE exome AF: 0.383

Gnomad4 OTH exome AF: 0.378

GnomAD4 genome AF: 0.325 AC: 49461 AN: 152054 Hom.: 8671 Cov.: 32 AF XY: 0.326 AC XY: 24256 AN XY: 74306

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.404

Gnomad4 EAS AF: 0.460

Gnomad4 SAS AF: 0.503

Gnomad4 FIN AF: 0.356

Gnomad4 NFE AF: 0.381

Gnomad4 OTH AF: 0.336

Alfa AF: 0.376 Hom.: 27122

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2019	- -

COMPLEMENT COMPONENT 8, ALPHA SUBUNIT, A/B POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Sep 01, 1995

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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 -

Type I complement component 8 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	7.5
Dann	Benign	0.65
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.00027	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.26	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.099
Sift	Benign	0.64	T
Sift4G	Benign	0.83	T
Polyphen		0.048	B
Vest4		0.051
MPC		0.037
ClinPred		0.0023	T
GERP RS		3.4
Varity_R		0.37
gMVP		0.47

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: rs652785; hg19: chr1-57340727; COSMIC: COSV63484431;