dbSNP rs9325622: CBS:c.1146-288T>C (chr21-43059591-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000071.3(CBS):c.1146-288T>C variant causes a intron 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 Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 112 hom., cov: 0)

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.678

Publications

9 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 21-43059591-A-G is Benign according to our data. Variant chr21-43059591-A-G is described in ClinVar as Benign. ClinVar VariationId is 670959.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	Effect	Exon Rank	Protein
CBS	NM_000071.3	MANE Select	c.1146-288T>C	intron	N/A	NP_000062.1
CBS	NM_001178008.3		c.1146-288T>C	intron	N/A	NP_001171479.1
CBS	NM_001178009.3		c.1146-288T>C	intron	N/A	NP_001171480.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CBS	ENST00000398165.8	TSL:1 MANE Select	c.1146-288T>C	intron	N/A	ENSP00000381231.4
CBS	ENST00000352178.9	TSL:1	c.1146-288T>C	intron	N/A	ENSP00000344460.5
CBS	ENST00000359624.7	TSL:1	c.1146-288T>C	intron	N/A	ENSP00000352643.3

Frequencies

GnomAD3 genomes

AF:

0.253

AC:

540

AN:

2134

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.385

Gnomad EAS

AF:

0.492

Gnomad SAS

AF:

0.286

Gnomad FIN

AF:

0.462

Gnomad MID

AF:

0.0385

Gnomad NFE

AF:

0.352

Gnomad OTH

AF:

0.196

GnomAD4 exome

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

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.251

AC:

534

AN:

2124

Hom.:

112

Cov.:

AF XY:

0.253

AC XY:

275

AN XY:

1086

show subpopulations

African (AFR)

AF:

0.100

AC:

AN:

610

American (AMR)

AF:

0.188

AC:

AN:

416

Ashkenazi Jewish (ASJ)

AF:

0.385

AC:

AN:

East Asian (EAS)

AF:

0.492

AC:

122

AN:

248

South Asian (SAS)

AF:

0.294

AC:

AN:

252

European-Finnish (FIN)

AF:

0.462

AC:

AN:

Middle Eastern (MID)

AF:

0.0417

AC:

AN:

European-Non Finnish (NFE)

AF:

0.356

AC:

165

AN:

464

Other (OTH)

AF:

0.196

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.334

Hom.:

1916

Asia WGS

AF:

0.423

AC:

1471

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.6

(source)

DANN

Benign

0.59

PhyloP100

-0.68

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over