rs181472622

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

The NM_000071.3(CBS):c.600G>A(p.Pro200Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 5)

Exomes 𝑓: 0.0000047 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -1.99

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

CBS links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000071.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 21-43065453-C-T is Benign according to our data. Variant chr21-43065453-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 340087.

BP7

Synonymous conserved (PhyloP=-1.99 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.600G>A	p.Pro200Pro	synonymous	Exon 7 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.600G>A	p.Pro200Pro	synonymous	Exon 7 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.600G>A	p.Pro200Pro	synonymous	Exon 7 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.600G>A	p.Pro200Pro	synonymous	Exon 7 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.600G>A	p.Pro200Pro	synonymous	Exon 7 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.600G>A	p.Pro200Pro	synonymous	Exon 7 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.000417

AC:

104

AN:

249506

AF XY:

0.000429

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00250

Gnomad NFE exome

AF:

0.000401

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000468

AC:

AN:

427724

Hom.:

Cov.:

AF XY:

0.00000439

AC XY:

AN XY:

227706

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13374

American (AMR)

AF:

0.00

AC:

AN:

29294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13950

East Asian (EAS)

AF:

0.00

AC:

AN:

31278

South Asian (SAS)

AF:

0.0000195

AC:

AN:

51348

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1842

European-Non Finnish (NFE)

AF:

0.00000425

AC:

AN:

235432

Other (OTH)

AF:

0.00

AC:

AN:

24124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000181

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

CBS-related disorder (1)

Classic homocystinuria (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

-0.79

CADD

Benign

1.4

(source)

DANN

Benign

0.71

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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