rs41286844

chr1-56940965-G-Achr1-56940965-G-Cchr1-56940965-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000066.4(C8B):c.1282C>T(p.Arg428Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,758 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 4 hom. )

Consequence

C8B
NM_000066.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 3.04

Variant links:

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]

C8B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 1-56940965-G-A is Pathogenic according to our data. Variant chr1-56940965-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-56940965-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
C8B	NM_000066.4 linkuse as main transcript	c.1282C>T	p.Arg428Ter	stop_gained	9/12	ENST00000371237.9
C8B	NM_001278543.2 linkuse as main transcript	c.1126C>T	p.Arg376Ter	stop_gained	10/13
C8B	NM_001278544.2 linkuse as main transcript	c.1096C>T	p.Arg366Ter	stop_gained	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C8B	ENST00000371237.9 linkuse as main transcript	c.1282C>T	p.Arg428Ter	stop_gained	9/12	1	NM_000066.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

195

AN:

151786

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000388

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000525

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00206

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.00112

AC:

281

AN:

251214

Hom.:

AF XY:

0.000972

AC XY:

132

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00188

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00133

AC:

1940

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

1003

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.000524

Gnomad4 NFE exome

AF:

0.00156

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.00128

AC:

194

AN:

151904

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00206

Gnomad4 OTH

AF:

0.000950

Alfa

AF:

0.00184

Hom.:

Bravo

AF:

0.00121

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00109

AC:

132

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29431110, 30609409, 31028847, 9476133, 14767900, 28192236, 8098723, 27183977, 25525159, 7594510, 19434484, 8020197, 9165271, 34426522, 31589614, 28368462, 33726816) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Arg428*) in the C8B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C8B are known to be pathogenic (PMID: 7594510). This variant is present in population databases (rs41286844, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with C8B deficiency (PMID: 8098723, 27183977). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17038). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Type II complement component 8 deficiency

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 29, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 27, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	May 08, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Aug 13, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 28, 2023	- -

Complement component 6 deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 24, 2014

The p.Arg428X variant in C8B has been reported in multiple individuals with clin ical features of C8B deficiency, including in >20 individuals who were homozygou s for this variant (Kaufmann, 1993; Saucedo, 1995). Homozygous and compound hete rozygous individuals were shown to have absent C8? activity. This variant has be en identified in 0.17% (112/66,626) of European chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP: rs41286844). This nonsense variant leads to a premature termination codon at position 428 which is predicted to lead to a truncated or absent protein. In summary, this variant me ets criteria to be classified as pathogenic based on case observations, function al evidence and predicted protein impact. -

C8B-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2023

The C8B c.1282C>T variant is predicted to result in premature protein termination (p.Arg428*). This variant has been reported in the homozygous and compound heterozygous state as causative for C8 deficiency (Kaufmann et al. 1993. PubMed ID: 8098723; Dellepiane et al. 2016. PubMed ID: 27183977). This variant is reported in 0.19% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-57406638-G-A). Nonsense variants in C8B are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/17038). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.94

MutationTaster

Benign

1.0

A;A;A

Vest4

0.80

GERP RS

3.5

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over