dbSNP rs2124459: CBS:c.1552+1199A>G (chr21-43055604-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.1552+1199A>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 0.36 ( 3017 hom., cov: 6)

Exomes 𝑓: 0.61 ( 173 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.68

Publications

20 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:

Genome browser will be placed here

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=-0.95).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.1552+1199A>G		intron_variant	Intron 16 of 16	ENST00000398165.8	NP_000062.1	P35520-1Q9NTF0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 link	c.1552+1199A>G		intron_variant	Intron 16 of 16	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

AF:

0.361

AC:

12933

AN:

35840

Hom.:

3015

Cov.:

show subpopulations

Gnomad AFR

AF:

0.153

Gnomad AMI

AF:

0.320

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.394

Gnomad EAS

AF:

0.609

Gnomad SAS

AF:

0.341

Gnomad FIN

AF:

0.546

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.430

Gnomad OTH

AF:

0.288

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.606

AC:

538

AN:

888

Hom.:

173

Cov.:

AF XY:

0.607

AC XY:

273

AN XY:

450

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.605

AC:

524

AN:

866

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AF:

0.750

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.360

AC:

12946

AN:

35918

Hom.:

3017

Cov.:

AF XY:

0.358

AC XY:

5896

AN XY:

16452

show subpopulations

African (AFR)

AF:

0.154

AC:

1042

AN:

6786

American (AMR)

AF:

0.210

AC:

854

AN:

4064

Ashkenazi Jewish (ASJ)

AF:

0.394

AC:

466

AN:

1184

East Asian (EAS)

AF:

0.608

AC:

786

AN:

1292

South Asian (SAS)

AF:

0.337

AC:

218

AN:

646

European-Finnish (FIN)

AF:

0.546

AC:

1041

AN:

1906

Middle Eastern (MID)

AF:

0.304

AC:

AN:

European-Non Finnish (NFE)

AF:

0.430

AC:

8337

AN:

19366

Other (OTH)

AF:

0.289

AC:

122

AN:

422

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

353

706

1059

1412

1765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<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:

0.408

Hom.:

19780

Asia WGS

AF:

0.518

AC:

1802

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.83

(source)

DANN

Benign

0.45

PhyloP100

-2.7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over