rs121909587
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_001735.3(C5):c.55C>T(p.Gln19*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000793 in 1,613,268 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 1 hom. )
Consequence
C5
NM_001735.3 stop_gained
NM_001735.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.79
Genes affected
C5 (HGNC:1331): (complement C5) This gene encodes a component of the complement system, a part of the innate immune system that plays an important role in inflammation, host homeostasis, and host defense against pathogens. The encoded preproprotein is proteolytically processed to generate multiple protein products, including the C5 alpha chain, C5 beta chain, C5a anaphylatoxin and C5b. The C5 protein is comprised of the C5 alpha and beta chains, which are linked by a disulfide bridge. Cleavage of the alpha chain by a convertase enzyme results in the formation of the C5a anaphylatoxin, which possesses potent spasmogenic and chemotactic activity, and the C5b macromolecular cleavage product, a subunit of the membrane attack complex (MAC). Mutations in this gene cause complement component 5 deficiency, a disease characterized by recurrent bacterial infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.989 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PP5
Variant 9-121050192-G-A is Pathogenic according to our data. Variant chr9-121050192-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
C5 | NM_001735.3 | c.55C>T | p.Gln19* | stop_gained | 1/41 | ENST00000223642.3 | NP_001726.2 | |
C5 | NM_001317164.2 | c.55C>T | p.Gln19* | stop_gained | 1/21 | NP_001304093.1 | ||
C5 | NM_001317163.2 | c.84-3809C>T | intron_variant | NP_001304092.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
C5 | ENST00000223642.3 | c.55C>T | p.Gln19* | stop_gained | 1/41 | 1 | NM_001735.3 | ENSP00000223642.1 |
Frequencies
GnomAD3 genomes AF: 0.000388 AC: 59AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000139 AC: 35AN: 251162Hom.: 1 AF XY: 0.0000737 AC XY: 10AN XY: 135752
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GnomAD4 exome AF: 0.0000465 AC: 68AN: 1460998Hom.: 1 Cov.: 30 AF XY: 0.0000385 AC XY: 28AN XY: 726854
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GnomAD4 genome AF: 0.000394 AC: 60AN: 152270Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29AN XY: 74434
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Complement component 5 deficiency Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | May 15, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 16, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 28, 2017 | The p.Gln19X variant in C5 has been reported in 3 families with C5 complement deficiency. In 1 family, the 2 affected members carried the variant in the homozygous state (Arnaout 2013), whereas in the remaining 2 families (Wang 1995, reported as(C84 AG to TAG) ) the variant was found in the heterozygous state in 6 affected individuals (presumably a second undetected variant was present on the other allele) . This variant has also been identified in 0.12% (29/24,032) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121909587). This nonsense variant leads to a premature termination codon at position 19, which is predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for C5 complement deficiency in an autosomal recessive manner based upon biallelic case observations, segregation studies and the nature of the variant (nonsense). - |
Complement component 5 deficiency;C3810402:Eculizumab, poor response to Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
Lathosterolosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Gln19*) in the C5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C5 are known to be pathogenic (PMID: 7730648, 19414197, 27026170). This variant is present in population databases (rs121909587, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with C5 deficiency and C5 deficiency in a family and has also been reported in individuals affected with C5 deficiency, including in the compound heterozygous state (PMID: 7730648, 23371790, 25534848). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Q1X. ClinVar contains an entry for this variant (Variation ID: 17050). For these reasons, this variant has been classified as Pathogenic. - |
C5-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 17, 2024 | The C5 c.55C>T variant is predicted to result in premature protein termination (p.Gln19*). This variant has been reported in the homozygous or compound heterozygous states in patients with C5 deficiency (Arnaout et al. 2013. PubMed ID: 23371790). This variant is reported in 0.13% of alleles in individuals of African descent in gnomAD. Nonsense variants in C5 are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Computational scores
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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
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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