rs766453711
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000071.3(CBS):c.738del(p.Lys247SerfsTer22) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 2)
Consequence
CBS
NM_000071.3 frameshift, splice_region
NM_000071.3 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.219
Genes affected
CBS (HGNC:1550): (cystathionine beta-synthase) The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by adenosyl-methionine and uses pyridoxal phosphate as a cofactor. Defects in this gene can cause cystathionine beta-synthase deficiency (CBSD), which can lead to homocystinuria. This gene is a major contributor to cellular hydrogen sulfide production. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 21-43063989-TC-T is Pathogenic according to our data. Variant chr21-43063989-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 370105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.738del | p.Lys247SerfsTer22 | frameshift_variant, splice_region_variant | 9/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.738del | p.Lys247SerfsTer22 | frameshift_variant, splice_region_variant | 9/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 2
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?
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2
GnomAD3 exomes AF: 0.00000411 AC: 1AN: 243362Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131722
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GnomAD4 exome Cov.: 0
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GnomAD4 genome ? Cov.: 2
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Classic homocystinuria Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 12, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Nov 18, 2015 | - - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change creates a premature translational stop signal (p.Lys247Serfs*22) 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). This variant is present in population databases (rs766453711, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 370105). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 14, 2023 | The CBS c.738del; p.Lys247SerfsTer22 variant (rs766453711) is reported in the literature in an individual with homocystinuria that carried an additional pathogenic variant (Allen 2019). This variant is reported in ClinVar (Variation ID: 370105) and is only observed on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, several downstream truncating variants have been described in individuals with homocystinuria and are considered pathogenic (Kraus 1999). The p.Lys247SerfsTer22 variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Allen J et al. Plasma methionine concentrations and incidence of hypermethioninemic encephalopathy during infancy in a large cohort of 36 patients with classical homocystinuria in the Republic of Ireland. JIMD Rep. 2019 Mar 26;47(1):41-46. PMID: 31240166. Kraus JP et al. Cystathionine beta-synthase mutations in homocystinuria. Hum Mutat. 1999;13(5):362-75. PMID: 10338090. - |
Computational scores
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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