rs121909587
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
Consequence
NM_001735.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
C5 | NM_001735.3 | c.55C>T | p.Gln19* | stop_gained | Exon 1 of 41 | ENST00000223642.3 | NP_001726.2 | |
C5 | NM_001317164.2 | c.55C>T | p.Gln19* | stop_gained | Exon 1 of 21 | NP_001304093.1 | ||
C5 | NM_001317163.2 | c.84-3809C>T | intron_variant | Intron 1 of 40 | NP_001304092.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000388 AC: 59AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251162Hom.: 1 AF XY: 0.0000737 AC XY: 10AN XY: 135752
GnomAD4 exome AF: 0.0000465 AC: 68AN: 1460998Hom.: 1 Cov.: 30 AF XY: 0.0000385 AC XY: 28AN XY: 726854
GnomAD4 genome AF: 0.000394 AC: 60AN: 152270Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29AN XY: 74434
ClinVar
Submissions by phenotype
Complement component 5 deficiency Pathogenic:3
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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
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Lathosterolosis Pathogenic:1
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not provided Pathogenic:1
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
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at