rs369220569

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PP2PP3_ModerateBS2_Supporting

The NM_000071.3(CBS):c.616G>A(p.Val206Met) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V206V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 5)

Exomes 𝑓: 0.000018 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.58

Publications

2 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: Uncertain_significance. The variant received 2 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8318 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to classic homocystinuria.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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
CBS	NM_000071.3	MANE Select	c.616G>A	p.Val206Met	missense	Exon 7 of 17	NP_000062.1
CBS	NM_001178008.3		c.616G>A	p.Val206Met	missense	Exon 7 of 17	NP_001171479.1
CBS	NM_001178009.3		c.616G>A	p.Val206Met	missense	Exon 7 of 18	NP_001171480.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CBS	ENST00000398165.8	TSL:1 MANE Select	c.616G>A	p.Val206Met	missense	Exon 7 of 17	ENSP00000381231.4
CBS	ENST00000352178.9	TSL:1	c.616G>A	p.Val206Met	missense	Exon 7 of 17	ENSP00000344460.5
CBS	ENST00000359624.7	TSL:1	c.616G>A	p.Val206Met	missense	Exon 7 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

19802

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

249812

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000356

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000183

AC:

AN:

435978

Hom.:

Cov.:

AF XY:

0.0000215

AC XY:

AN XY:

232834

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13592

American (AMR)

AF:

0.00

AC:

AN:

30418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14568

East Asian (EAS)

AF:

0.00

AC:

AN:

31298

South Asian (SAS)

AF:

0.00

AC:

AN:

53592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1892

European-Non Finnish (NFE)

AF:

0.0000335

AC:

AN:

238590

Other (OTH)

AF:

0.00

AC:

AN:

24342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

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: AC0;AS_VQSR

AF:

0.00

AC:

AN:

19802

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

9326

African (AFR)

AF:

0.00

AC:

AN:

4816

American (AMR)

AF:

0.00

AC:

AN:

2126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

550

East Asian (EAS)

AF:

0.00

AC:

AN:

1010

South Asian (SAS)

AF:

0.00

AC:

AN:

360

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

9138

Other (OTH)

AF:

0.00

AC:

AN:

200

Alfa

AF:

0.0000712

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Classic homocystinuria (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.9

PhyloP100

6.6

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.79

Sift

Uncertain

0.013

Sift4G

Uncertain

0.014

Polyphen

0.97

Vest4

0.88

MVP

0.94

MPC

1.0

ClinPred

0.86

GERP RS

4.7

Varity_R

0.67

gMVP

0.84

Mutation Taster

=17/83

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over