chr21-43053880-T-G
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4
The NM_000071.3(CBS):c.1656A>C(p.Ter552CysextTer31) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 0)
Consequence
CBS
NM_000071.3 stop_lost
NM_000071.3 stop_lost
Scores
1
6
Clinical Significance
Conservation
PhyloP100: -0.162
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 Uncertain_significance. Variant got 2 ACMG points.
PM4
Stoplost variant in NM_000071.3 Downstream stopcodon found after 22 codons.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.1656A>C | p.Ter552CysextTer31 | stop_lost | 17/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.1656A>C | p.Ter552CysextTer31 | stop_lost | 17/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 0
GnomAD3 genomes
Cov.:
0
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 247976Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134466
GnomAD3 exomes
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1
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247976
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134466
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GnomAD4 exome Cov.: 0
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GnomAD4 genome Cov.: 0
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Classic homocystinuria Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 10, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 19, 2021 | - - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 12, 2018 | This variant has not been reported in the literature in individuals with CBS-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency). This sequence change disrupts the translational stop signal of the CBS mRNA. It is expected to extend the length of the CBS protein by 31 additional amino acid residues. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
N;N;N;N;N;N;N;N;N;N;N;N
Vest4
GERP RS
Splicing
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Calibrated prediction
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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