21-43072174-TG-TGG
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000071.3(CBS):c.19dupC(p.Gln7ProfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000071.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 0
GnomAD3 exomes AF: 0.00000411 AC: 1AN: 243178Hom.: 0 AF XY: 0.00000752 AC XY: 1AN XY: 132972
GnomAD4 exome Cov.: 0
GnomAD4 genome Cov.: 0
ClinVar
Submissions by phenotype
Classic homocystinuria Pathogenic:5
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HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gln7Profs*30) in the CBS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CBS are known to be pathogenic (PMID: 10338090, 12124992). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with CBS deficiency (PMID: 10338090, 12124992). ClinVar contains an entry for this variant (Variation ID: 371345). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10338090, 31589614, 25218699) -
CBS-related disorder Pathogenic:1
The CBS c.19dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln7Profs*30). This variant has been reported in both the homozygous and compound heterozygous states in multiple individuals with homocystinuria (referred to as 19insC in Kraus et al. 1999. PubMed ID: 10338090; Gaustadnes et al. 2002. PubMed ID: 12124992; Janosík et al. 2001. PubMed ID: 11359213; Alcaide et al. 2014. PubMed ID: 25218699). This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD. Frameshift variants in CBS are expected to be pathogenic. This variant is interpreted as pathogenic. -
Homocystinuria Pathogenic:1
Variant summary: CBS c.19dupC (p.Gln7ProfsX30) 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 4.1e-06 in 243178 control chromosomes (gnomAD). c.19dupC has been reported in the literature in multiple homozygote and compound heterozygote individuals affected with Homocystinuria (Alcaide_2015, Gaustadnes_2002). These data indicate that the variant is very likely to be associated with disease. A compound heterozygote affected individual was found to have <10% CBS activity (Alcaide_2015). Three ClinVar submisions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at