dbSNP rs1347651454: CBS:p.Cys165Tyr (chr21-43065653-C-T) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):c.494G>A(p.Cys165Tyr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C165G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.78

Publications

10 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

CBS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000071.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43065654-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 580466.Status of the report is criteria_provided_single_submitter, 1 stars.

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, 0.985

PP5

Variant 21-43065653-C-T is Pathogenic according to our data. Variant chr21-43065653-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 495531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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	UniProt
CBS	NM_000071.3	MANE Select	c.494G>A	p.Cys165Tyr	missense	Exon 6 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.494G>A	p.Cys165Tyr	missense	Exon 6 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.494G>A	p.Cys165Tyr	missense	Exon 6 of 18	NP_001171480.1	P35520-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CBS	ENST00000398165.8	TSL:1 MANE Select	c.494G>A	p.Cys165Tyr	missense	Exon 6 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.494G>A	p.Cys165Tyr	missense	Exon 6 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.494G>A	p.Cys165Tyr	missense	Exon 6 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000544

AC:

AN:

183760

AF XY:

0.0000102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000131

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

290772

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

153218

African (AFR)

AF:

0.00

AC:

AN:

8950

American (AMR)

AF:

0.00

AC:

AN:

14342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8230

East Asian (EAS)

AF:

0.00

AC:

AN:

24574

South Asian (SAS)

AF:

0.00

AC:

AN:

40310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1212

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

159808

Other (OTH)

AF:

0.00

AC:

AN:

16494

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Classic homocystinuria (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

Homocystinuria (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

PhyloP100

6.8

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-9.8

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MVP

0.93

MPC

1.5

ClinPred

1.0

GERP RS

4.6

Varity_R

0.99

gMVP

0.96

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

3.0

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