dbSNP rs234706: CBS:p.Tyr233Tyr (chr21-43065240-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7

The NM_000071.3(CBS):c.699C>T(p.Tyr233Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: not found (cov: 16)

Consequence

CBS
NM_000071.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -0.907

Publications

84 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 21-43065240-G-A is Benign according to our data. Variant chr21-43065240-G-A is described in ClinVar as Benign. ClinVar VariationId is 92426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.907 with no splicing effect.

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.699C>T	p.Tyr233Tyr	synonymous	Exon 8 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.699C>T	p.Tyr233Tyr	synonymous	Exon 8 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.699C>T	p.Tyr233Tyr	synonymous	Exon 8 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.699C>T	p.Tyr233Tyr	synonymous	Exon 8 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.699C>T	p.Tyr233Tyr	synonymous	Exon 8 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.699C>T	p.Tyr233Tyr	synonymous	Exon 8 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.274

AC:

68736

AN:

251310

AF XY:

0.279

show subpopulations

Gnomad AFR exome

AF:

0.231

Gnomad AMR exome

AF:

0.185

Gnomad ASJ exome

AF:

0.350

Gnomad EAS exome

AF:

0.0230

Gnomad FIN exome

AF:

0.277

Gnomad NFE exome

AF:

0.345

Gnomad OTH exome

AF:

0.288

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.323

Hom.:

26066

Asia WGS

AF:

0.147

AC:

512

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Classic homocystinuria (5)

not provided (2)

Connective tissue disorder (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

2.6

(source)

DANN

Benign

0.56

PhyloP100

-0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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