1-56956811-C-T

Position:

• chr1-56956811-C-T

Variant summary

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

The NM_000066.4(C8B):​c.349G>A​(p.Gly117Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.973 in 1,614,046 control chromosomes in the GnomAD database, including 764,602 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.98 (72967 hom., cov: 31)
  • Exomes 𝑓: 0.97 (691635 hom.)
• Consequence: C8B NM_000066.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.950

Genes affected

C8B (HGNC:1353): (complement C8 beta chain) This gene encodes one of the three subunits of the complement component 8 (C8) protein. C8 is composed of equimolar amounts of alpha, beta and gamma subunits, which are encoded by three separate genes. C8 is one component of the membrane attack complex, which mediates cell lysis, and it initiates membrane penetration of the complex. This protein mediates the interaction of C8 with the C5b-7 membrane attack complex precursor. In humans deficiency of this protein is associated with increased risk of meningococcal infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.8007174E-7).
• BP6: Variant 1-56956811-C-T is Benign according to our data. Variant chr1-56956811-C-T is described in ClinVar as [Benign]. Clinvar id is 1169777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-56956811-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C8B	NM_000066.4	c.349G>A	p.Gly117Arg	missense_variant	3/12	ENST00000371237.9	NP_000057.3
C8B	NM_001278543.2	c.193G>A	p.Gly65Arg	missense_variant	4/13		NP_001265472.2
C8B	NM_001278544.2	c.163G>A	p.Gly55Arg	missense_variant	4/13		NP_001265473.2
C8B	XM_047429957.1	c.349G>A	p.Gly117Arg	missense_variant	3/7		XP_047285913.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C8B	ENST00000371237.9	c.349G>A	p.Gly117Arg	missense_variant	3/12	1	NM_000066.4	ENSP00000360281	P1

Frequencies

GnomAD3 genomes AF: 0.979 AC: 148906 AN: 152126 Hom.: 72908 Cov.: 31

Gnomad AFR AF: 0.994

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.973

Gnomad ASJ AF: 0.970

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.989

Gnomad FIN AF: 0.985

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.968

Gnomad OTH AF: 0.973

GnomAD3 exomes AF: 0.977 AC: 245666 AN: 251372 Hom.: 120098 AF XY: 0.977 AC XY: 132678 AN XY: 135850

Gnomad AFR exome AF: 0.994

Gnomad AMR exome AF: 0.975

Gnomad ASJ exome AF: 0.974

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.990

Gnomad FIN exome AF: 0.982

Gnomad NFE exome AF: 0.968

Gnomad OTH exome AF: 0.967

GnomAD4 exome AF: 0.973 AC: 1421897 AN: 1461802 Hom.: 691635 Cov.: 50 AF XY: 0.973 AC XY: 707467 AN XY: 727216

Gnomad4 AFR exome AF: 0.995

Gnomad4 AMR exome AF: 0.974

Gnomad4 ASJ exome AF: 0.972

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.988

Gnomad4 FIN exome AF: 0.980

Gnomad4 NFE exome AF: 0.969

Gnomad4 OTH exome AF: 0.974

GnomAD4 genome AF: 0.979 AC: 149024 AN: 152244 Hom.: 72967 Cov.: 31 AF XY: 0.980 AC XY: 72926 AN XY: 74418

Gnomad4 AFR AF: 0.994

Gnomad4 AMR AF: 0.973

Gnomad4 ASJ AF: 0.970

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.989

Gnomad4 FIN AF: 0.985

Gnomad4 NFE AF: 0.968

Gnomad4 OTH AF: 0.973

Alfa AF: 0.969 Hom.: 174819

Bravo AF: 0.978

TwinsUK AF: 0.970 AC: 3596

ALSPAC AF: 0.977 AC: 3765

ESP6500AA AF: 0.993 AC: 4373

ESP6500EA AF: 0.967 AC: 8318

ExAC AF: 0.977 AC: 118661

Asia WGS AF: 0.995 AC: 3462 AN: 3478

EpiCase AF: 0.965

EpiControl AF: 0.966

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Type II 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	0.042
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.8
DANN	Benign	0.53
DEOGEN2	Benign	0.0014	.;T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.048	.;T;T
MetaRNN	Benign	5.8e-7	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	2.9	N;N;N
REVEL	Benign	0.036
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.76	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.081
MutPred		0.32		.;.;Gain of disorder (P = 0.0794);
MPC		0.041
ClinPred		0.0050	T
GERP RS		-0.17
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1013579; hg19: chr1-57422484;