Genetic Variant CBS:c.1552+1117A>G (chr21-43055686-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+1117A>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 0.63 ( 20895 hom., cov: 11)

Exomes 𝑓: 0.68 ( 7778 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.692

Publications

10 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=-0.91).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.1552+1117A>G		intron_variant	Intron 16 of 16	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 link	c.1552+1117A>G		intron_variant	Intron 16 of 16	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes

AF:

0.633

AC:

58571

AN:

92516

Hom.:

20885

Cov.:

show subpopulations

Gnomad AFR

AF:

0.663

Gnomad AMI

AF:

0.495

Gnomad AMR

AF:

0.445

Gnomad ASJ

AF:

0.625

Gnomad EAS

AF:

0.631

Gnomad SAS

AF:

0.519

Gnomad FIN

AF:

0.642

Gnomad MID

AF:

0.495

Gnomad NFE

AF:

0.673

Gnomad OTH

AF:

0.603

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.679

AC:

21371

AN:

31452

Hom.:

7778

Cov.:

AF XY:

0.673

AC XY:

11758

AN XY:

17480

show subpopulations

African (AFR)

AF:

0.721

AC:

215

AN:

298

American (AMR)

AF:

0.427

AC:

474

AN:

1110

Ashkenazi Jewish (ASJ)

AF:

0.703

AC:

343

AN:

488

East Asian (EAS)

AF:

0.689

AC:

423

AN:

614

South Asian (SAS)

AF:

0.606

AC:

3646

AN:

6012

European-Finnish (FIN)

AF:

0.684

AC:

7367

AN:

10772

Middle Eastern (MID)

AF:

0.584

AC:

264

AN:

452

European-Non Finnish (NFE)

AF:

0.740

AC:

7941

AN:

10724

Other (OTH)

AF:

0.711

AC:

698

AN:

982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.534

Heterozygous variant carriers

277

553

830

1106

1383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.633

AC:

58605

AN:

92578

Hom.:

20895

Cov.:

AF XY:

0.624

AC XY:

27644

AN XY:

44276

show subpopulations

African (AFR)

AF:

0.663

AC:

12897

AN:

19446

American (AMR)

AF:

0.444

AC:

4723

AN:

10630

Ashkenazi Jewish (ASJ)

AF:

0.625

AC:

1569

AN:

2512

East Asian (EAS)

AF:

0.631

AC:

2295

AN:

3636

South Asian (SAS)

AF:

0.519

AC:

1447

AN:

2790

European-Finnish (FIN)

AF:

0.642

AC:

3679

AN:

5728

Middle Eastern (MID)

AF:

0.510

AC:

105

AN:

206

European-Non Finnish (NFE)

AF:

0.674

AC:

30864

AN:

45818

Other (OTH)

AF:

0.600

AC:

741

AN:

1236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

741

1482

2223

2964

3705

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

454

908

1362

1816

2270

<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:

0.664

Hom.:

4324

Asia WGS

AF:

0.606

AC:

2109

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

3.6

(source)

DANN

Benign

0.52

PhyloP100

0.69

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over