rs146187042

Positions:

chr1-56956889-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000066.4(C8B):c.271C>T(p.Gln91Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000338 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

C8B
NM_000066.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.98

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 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-56956889-G-A is Pathogenic according to our data. Variant chr1-56956889-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-56956889-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
C8B	NM_000066.4 linkuse as main transcript	c.271C>T	p.Gln91Ter	stop_gained	3/12	ENST00000371237.9	NP_000057.3
C8B	NM_001278543.2 linkuse as main transcript	c.115C>T	p.Gln39Ter	stop_gained	4/13		NP_001265472.2
C8B	NM_001278544.2 linkuse as main transcript	c.85C>T	p.Gln29Ter	stop_gained	4/13		NP_001265473.2
C8B	XM_047429957.1 linkuse as main transcript	c.271C>T	p.Gln91Ter	stop_gained	3/7		XP_047285913.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C8B	ENST00000371237.9 linkuse as main transcript	c.271C>T	p.Gln91Ter	stop_gained	3/12	1	NM_000066.4	ENSP00000360281	P1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251224

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000350

AC:

512

AN:

1461822

Hom.:

Cov.:

AF XY:

0.000329

AC XY:

239

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000446

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000217

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000367

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000288

Hom.:

Bravo

AF:

0.000140

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change creates a premature translational stop signal (p.Gln91*) 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 (rs146187042, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with complement C8b deficiency (PMID: 7594510, 14767900, 19434484). This variant is also known as 298C>T. ClinVar contains an entry for this variant (Variation ID: 35594). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 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: 7594510, 25525159, 14767900, 30609409, 19434484, 31980526, 34285166, 28368462) -

Type II complement component 8 deficiency

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 29, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -

Complement component 6 deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 27, 2017

The p.Gln91X (NM_000066.2 c.271C>T)(legacy p.Gln37Term) variant in C8B has been previously reported in 3 compound heterozygous individuals with complement C8b d eficiency, and susceptibility to recurrent neisserial infections, predominantly with meningococcus infection of rare serotypes (Arnold 2009, Rao 2004 and Sauced o 1995). This variant also segregated in 3 siblings from 1 family (Saucedo 1995) . Patient serum testing for C8B activity of the p.GlnX variant report an impact to protein activity (Saucedo 1995), however no truncated protein was detected by in vitro functional studies, suggesting the variant confers protein instability or the transcripts are degraded via nonsense mediated decay (Arnold 1999). This variant has been identified in 28/126,486 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1461870 42). Although this variant has been seen in the general population, its frequenc y is low enough to be consistent with a recessive carrier frequency. Biallelic l oss of function of the C8B gene has been associated with complement C8b deficien cy. In summary, the p.Gln91X variant is pathogenic for complement C8b deficiency in an autosomal recessive manner based on protein studies, biallelic occurrence in individuals with this disease and segregation data. -

C8B-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2023

The C8B c.271C>T variant is predicted to result in premature protein termination (p.Gln91*). This variant was reported in the compound heterozygous state with another C8B frameshift variant an individual with complement C8b deficiency (Arnold et al. 2009. PubMed ID: 19434484). It was also reported in the heterozygous state in an individual with a terminal complement pathway deficiency, although no additional genetic evidence was provided for the reported patient (see Figure 2 and Supplementary Table 1 for Rosain et al.2017. PubMed ID: 28368462). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-57422562-G-A). Nonsense variants in C8B are expected to be pathogenic. In summary, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.072

FATHMM_MKL

Benign

0.71

MutationTaster

Benign

1.0

A;A;A

Vest4

0.78

GERP RS

2.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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