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rs150022116

chr1-56956799-G-Achr1-56956799-G-Cchr1-56956799-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000066.4(C8B):c.361C>T(p.Arg121Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,613,906 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R121R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

C8B
NM_000066.4 stop_gained

Scores

3
2
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 1.36
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-56956799-G-A is Pathogenic according to our data. Variant chr1-56956799-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35593.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
C8BNM_000066.4 linkuse as main transcriptc.361C>T p.Arg121Ter stop_gained 3/12 ENST00000371237.9
C8BNM_001278543.2 linkuse as main transcriptc.205C>T p.Arg69Ter stop_gained 4/13
C8BNM_001278544.2 linkuse as main transcriptc.175C>T p.Arg59Ter stop_gained 4/13
C8BXM_047429957.1 linkuse as main transcriptc.361C>T p.Arg121Ter stop_gained 3/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
C8BENST00000371237.9 linkuse as main transcriptc.361C>T p.Arg121Ter stop_gained 3/121 NM_000066.4 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000461
AC:
7
AN:
152000
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000135
AC:
34
AN:
251312
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135816
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.000794
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000185
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000978
AC:
143
AN:
1461788
Hom.:
0
Cov.:
30
AF XY:
0.000102
AC XY:
74
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.000421
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000998
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000460
AC:
7
AN:
152118
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000194
Hom.:
0
Bravo
AF:
0.0000718
ExAC
?
    Exome Aggregation Consortium database
AF:
0.000107
AC:
13
EpiCase
AF:
0.000164
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Type II complement component 8 deficiency Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 15, 2024Variant summary: C8B c.361C>T (p.Arg121X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00014 in 251312 control chromosomes (gnomAD). c.361C>T (also known as 388C>T) has been reported in the literature in multiple individuals affected with Type II Complement Component 8 Deficiency (examples: Saucedo_1995, Sissy_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31440263, 7594510). These data indicate that the variant is very likely to be associated with disease. ClinVar contains an entry for this variant (Variation ID: 35593). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 2009- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeOct 07, 2022This sequence change creates a premature translational stop signal (p.Arg121*) 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 (rs150022116, gnomAD 0.09%). This premature translational stop signal has been observed in individual(s) with C8B-related conditions (PMID: 7594510, 31440263). This variant is also known as 388C>T. ClinVar contains an entry for this variant (Variation ID: 35593). For these reasons, this variant has been classified as Pathogenic. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMay 03, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.60
Cadd
Pathogenic
38
Dann
Uncertain
1.0
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Benign
0.29
N
MutationTaster
Benign
1.0
A;A;A
Vest4
0.90
GERP RS
5.4

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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: rs150022116; hg19: chr1-57422472; COSMIC: COSV64776847; COSMIC: COSV64776847; API