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
Consequence
NM_000066.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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C8B | NM_000066.4 | c.1282C>T | p.Arg428* | stop_gained | Exon 9 of 12 | ENST00000371237.9 | NP_000057.3 | |
C8B | NM_001278543.2 | c.1126C>T | p.Arg376* | stop_gained | Exon 10 of 13 | NP_001265472.2 | ||
C8B | NM_001278544.2 | c.1096C>T | p.Arg366* | stop_gained | Exon 10 of 13 | NP_001265473.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00128 AC: 195AN: 151786Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00112 AC: 281AN: 251214Hom.: 0 AF XY: 0.000972 AC XY: 132AN XY: 135756
GnomAD4 exome AF: 0.00133 AC: 1940AN: 1461854Hom.: 4 Cov.: 32 AF XY: 0.00138 AC XY: 1003AN XY: 727230
GnomAD4 genome AF: 0.00128 AC: 194AN: 151904Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87AN XY: 74238
ClinVar
Submissions by phenotype
Type II complement component 8 deficiency Pathogenic:7
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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. -
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
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not provided Pathogenic:7
C8B: PVS1, PM3, PP1:Moderate, PM2:Supporting -
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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) -
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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. -
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Complement component 6 deficiency Pathogenic:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at