dbSNP rs9982015: CBS:c.210-1367A>G (chr21-43069982-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000071.3(CBS):c.210-1367A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0034 ( 11 hom., cov: 5)

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 intron

Scores

Splicing: ADA: 0.0001699

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.48

Publications

7 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 -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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	Effect	Exon Rank	Protein	UniProt
CBS	NM_000071.3	MANE Select	c.210-1367A>G	intron	N/A	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.210-1367A>G	intron	N/A	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.210-1367A>G	intron	N/A	NP_001171480.1	P35520-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CBS	ENST00000398165.8	TSL:1 MANE Select	c.210-1367A>G	intron	N/A	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.210-1367A>G	intron	N/A	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.210-1367A>G	intron	N/A	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

AF:

0.00344

AC:

136

AN:

39548

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.000828

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0185

Gnomad NFE

AF:

0.000247

Gnomad OTH

AF:

0.00644

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00341

AC:

135

AN:

39586

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

AN XY:

18868

show subpopulations

African (AFR)

AF:

0.0154

AC:

116

AN:

7514

American (AMR)

AF:

0.00242

AC:

AN:

4136

Ashkenazi Jewish (ASJ)

AF:

0.000828

AC:

AN:

1208

East Asian (EAS)

AF:

0.00

AC:

AN:

2542

South Asian (SAS)

AF:

0.00

AC:

AN:

946

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000247

AC:

AN:

20206

Other (OTH)

AF:

0.00630

AC:

AN:

476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0277

Hom.:

Asia WGS

AF:

0.0310

AC:

108

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.091

(source)

DANN

Benign

0.45

PhyloP100

-1.5

Mutation Taster

=298/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00017

dbscSNV1_RF

Benign

0.014

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over