rs2298758
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_000071.3(CBS):āc.636C>Gā(p.Asn212Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ). Synonymous variant affecting the same amino acid position (i.e. N212N) has been classified as Benign.
Frequency
Genomes: not found (cov: 5)
Exomes š: 0.00019 ( 19 hom. )
Failed GnomAD Quality Control
Consequence
CBS
NM_000071.3 missense
NM_000071.3 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: -0.783
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 Likely_benign. Variant got -4 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.051193625).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.636C>G | p.Asn212Lys | missense_variant | 7/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.636C>G | p.Asn212Lys | missense_variant | 7/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 5
GnomAD3 genomes
Cov.:
5
GnomAD3 exomes AF: 0.000116 AC: 29AN: 250098Hom.: 0 AF XY: 0.000185 AC XY: 25AN XY: 135358
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000187 AC: 84AN: 448080Hom.: 19 Cov.: 4 AF XY: 0.000321 AC XY: 77AN XY: 239924
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome Cov.: 5
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5
ExAC
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17
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Classic homocystinuria Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2014 | p.Asn212Lys (AAC>AAG): c.636 C>G in exon 7 of the CBS gene (NM_000071.2). A variant of unknown significance has been identified in the CBS gene. To our knowledge, the N212K variant has not been published as a disease-causing mutation nor as a benign polymorphism to our knowledge. The N212K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N212K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is mostly conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense mutation in nearby residue (S217F) has been reported in association with homocystinuria, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAAD - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;D;D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
.;.;.;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;N;N
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
B;B;B;B
Vest4
MutPred
Gain of ubiquitination at N212 (P = 0.0289);Gain of ubiquitination at N212 (P = 0.0289);Gain of ubiquitination at N212 (P = 0.0289);Gain of ubiquitination at N212 (P = 0.0289);
MVP
MPC
0.40
ClinPred
T
GERP RS
Varity_R
gMVP
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