Genetic Variant CBS:p.Gly532Arg (chr21-43053942-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2PP3

The NM_000071.3(CBS):c.1594G>A(p.Gly532Arg) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G532W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 0)

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.58

Publications

0 publications found

Variant links:

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]

CBS Gene-Disease associations (from GenCC):

classic homocystinuria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, PanelApp Australia, ClinGen, Genomics England PanelApp

CBS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8318 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to classic homocystinuria.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.79

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000071.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CBS	NM_000071.3	MANE Select	c.1594G>A	p.Gly532Arg	missense	Exon 17 of 17	NP_000062.1
CBS	NM_001178008.3		c.1594G>A	p.Gly532Arg	missense	Exon 17 of 17	NP_001171479.1
CBS	NM_001178009.3		c.1594G>A	p.Gly532Arg	missense	Exon 17 of 18	NP_001171480.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CBS	ENST00000398165.8	TSL:1 MANE Select	c.1594G>A	p.Gly532Arg	missense	Exon 17 of 17	ENSP00000381231.4
CBS	ENST00000352178.9	TSL:1	c.1594G>A	p.Gly532Arg	missense	Exon 17 of 17	ENSP00000344460.5
CBS	ENST00000359624.7	TSL:1	c.1594G>A	p.Gly532Arg	missense	Exon 17 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000960

AC:

AN:

249962

AF XY:

0.0000664

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00120

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000741

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Classic homocystinuria (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

Eigen

Benign

0.063

Eigen_PC

Benign

-0.0046

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.7

PhyloP100

4.6

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.9

REVEL

Uncertain

0.64

Sift

Uncertain

0.012

Sift4G

Uncertain

0.029

Polyphen

0.68

Vest4

0.58

MutPred

0.90

Gain of MoRF binding (P = 0.0094)

MVP

0.86

MPC

0.62

ClinPred

0.51

GERP RS

3.4

Varity_R

0.87

gMVP

0.97

Mutation Taster

=24/76

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over