rs1000697114

Variant names:

• chr21-43063962-C-T
• rs1000697114
• NM_000071.3:c.766G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_Strong PP5_Moderate

The NM_000071.3(CBS):​c.766G>A​(p.Gly256Ser) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 3)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.85

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.997
• PP5: Variant 21-43063962-C-T is Pathogenic according to our data. Variant chr21-43063962-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 573223.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.766G>A	p.Gly256Ser	missense_variant	Exon 9 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.766G>A	p.Gly256Ser	missense_variant	Exon 9 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 3

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Sep 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 573223). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 256 of the CBS protein (p.Gly256Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CBS-related conditions (Invitae). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	.;.;.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	1.0	D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.0	M;M;M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.98
MutPred		0.98		Gain of glycosylation at G256 (P = 0.1447);Gain of glycosylation at G256 (P = 0.1447);Gain of glycosylation at G256 (P = 0.1447);Gain of glycosylation at G256 (P = 0.1447);
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1000697114; hg19: chr21-44484072;