rs41286844

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.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

2
4
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

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]

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 rank MANE Protein UniProt
C8BNM_000066.4 linkc.1282C>T p.Arg428* stop_gained Exon 9 of 12 ENST00000371237.9 NP_000057.3 P07358
C8BNM_001278543.2 linkc.1126C>T p.Arg376* stop_gained Exon 10 of 13 NP_001265472.2 B7Z555
C8BNM_001278544.2 linkc.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
C8BENST00000371237.9 linkc.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.:
0
Cov.:
32
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.:
0
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.:
4
Cov.:
32
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.:
0
Cov.:
32
AF XY:
0.00117
AC XY:
87
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.:
3
Bravo
AF:
0.00121
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00233
AC:
20
ExAC
AF:
0.00109
AC:
132
Asia WGS
AF:
0.000289
AC:
1
AN:
3476

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Type II complement component 8 deficiency Pathogenic:7
Mar 28, 2023
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 01, 2009
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

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. -

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]. -

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

- -

Aug 13, 2019
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Pathogenic:7
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 -

Aug 08, 2018
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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) -

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

-
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

- -

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
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
40
DANN
Uncertain
1.0
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.94
D
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.

Other links and lift over

dbSNP: rs41286844; hg19: chr1-57406638; COSMIC: COSV64777577; API