rs121909594
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001737.5(C9):c.1280C>G(p.Ser427Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000521 in 1,612,574 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
C9
NM_001737.5 stop_gained
NM_001737.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.94
Genes affected
C9 (HGNC:1358): (complement C9) This gene encodes the final component of the complement system. It participates in the formation of the Membrane Attack Complex (MAC). The MAC assembles on bacterial membranes to form a pore, permitting disruption of bacterial membrane organization. Mutations in this gene cause component C9 deficiency. [provided by RefSeq, Feb 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 5-39306753-G-C is Pathogenic according to our data. Variant chr5-39306753-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 17043.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
C9 | NM_001737.5 | c.1280C>G | p.Ser427Ter | stop_gained | 9/11 | ENST00000263408.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
C9 | ENST00000263408.5 | c.1280C>G | p.Ser427Ter | stop_gained | 9/11 | 1 | NM_001737.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152118Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250674Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135432
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GnomAD4 exome AF: 0.0000534 AC: 78AN: 1460338Hom.: 0 Cov.: 29 AF XY: 0.0000564 AC XY: 41AN XY: 726518
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74424
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Complement component 9 deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1998 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Ser427*) in the C9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C9 are known to be pathogenic (PMID: 9144525, 9570574). This variant is present in population databases (rs121909594, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with complement C9 deficiency (PMID: 9634479). It has also been observed to segregate with disease in related individuals. This variant is also known as Ser406*. ClinVar contains an entry for this variant (Variation ID: 17043). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at