rs41286844

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS2_Supporting

The NM_000066.4(C8B):c.1282C>T(p.Arg428*) 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:17

Conservation

PhyloP100: 3.04

Publications

26 publications found

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 Gene-Disease associations (from GenCC):

type II complement component 8 deficiency
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

C8B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 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 VariationId is 17038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 4 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C8B	NM_000066.4 link	c.1282C>T	p.Arg428*	stop_gained	Exon 9 of 12	ENST00000371237.9	NP_000057.3	P07358
C8B	NM_001278543.2 link	c.1126C>T	p.Arg376*	stop_gained	Exon 10 of 13		NP_001265472.2	B7Z555
C8B	NM_001278544.2 link	c.1096C>T	p.Arg366*	stop_gained	Exon 10 of 13		NP_001265473.2	B7Z550

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C8B	ENST00000371237.9 link	c.1282C>T	p.Arg428*	stop_gained	Exon 9 of 12	1	NM_000066.4	ENSP00000360281.4		P07358

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

GnomAD2 exomes

AF:

0.00112

AC:

281

AN:

251214

AF XY:

0.000972

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 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

African (AFR)

AF:

0.000239

AC:

AN:

33476

American (AMR)

AF:

0.000850

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.000359

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000524

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00156

AC:

1732

AN:

1111992

Other (OTH)

AF:

0.00129

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

113

227

340

454

567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00128

AC:

194

AN:

151904

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.000386

AC:

AN:

41406

American (AMR)

AF:

0.000524

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.00125

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00206

AC:

140

AN:

67954

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00183

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:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Type II complement component 8 deficiency

Pathogenic:8

Aug 25, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Sep 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jul 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 08, 2023

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 28, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 27, 2019

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Aug 13, 2019

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 25, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The C8B c.1282C>T (p.Arg428Ter) variant has been reported in more than 20 individuals who were homozygous for this variant and affected with C8 deficiency and is reported to segregate with disease in related individuals (Dellepiane RM et al., PMID: 27183977; Kaufmann T et al., PMID: 8098723; Kotnik V et al., PMID: 9476133; Sanges S et al., PMID: 28192236; Saucedo L et al., PMID: 7594510). This variant is predicted to result in nonsense mediated decay and loss of function is the known mechanism of disease (Saucedo L et al., PMID: 7594510). The highest population minor allele frequency in the population genome aggregation database (v.2.1.1) is 0.189%, which is higher than the incidence of C8 deficiency. This variant has been reported in the ClinVar database as a pathogenic variant in patients with type II complement component 8 deficiency by 13 submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

not provided

Pathogenic:7

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

C8B: PVS1, PM3, PP1:Moderate, PM2:Supporting -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 15, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Aug 08, 2018

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Complement component 6 deficiency

Pathogenic:1

Apr 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 29, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. 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

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.94

PhyloP100

3.0

Vest4

0.80

GERP RS

3.5

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over