dbSNP rs786204579: CBS:p.Arg121His (chr21-43066332-C-T) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):c.362G>A(p.Arg121His) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R121G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 9)

Exomes 𝑓: 0.0000088 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.84

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000071.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43066333-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2913713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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, 0.95

PP5

Variant 21-43066332-C-T is Pathogenic according to our data. Variant chr21-43066332-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188948.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	HGVSp	Effect	Exon Rank	Protein
CBS	NM_000071.3	MANE Select	c.362G>A	p.Arg121His	missense	Exon 5 of 17	NP_000062.1
CBS	NM_001178008.3		c.362G>A	p.Arg121His	missense	Exon 5 of 17	NP_001171479.1
CBS	NM_001178009.3		c.362G>A	p.Arg121His	missense	Exon 5 of 18	NP_001171480.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CBS	ENST00000398165.8	TSL:1 MANE Select	c.362G>A	p.Arg121His	missense	Exon 5 of 17	ENSP00000381231.4
CBS	ENST00000352178.9	TSL:1	c.362G>A	p.Arg121His	missense	Exon 5 of 17	ENSP00000344460.5
CBS	ENST00000359624.7	TSL:1	c.362G>A	p.Arg121His	missense	Exon 5 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

74826

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:

0.0000239

AC:

AN:

251070

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.000185

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000885

AC:

AN:

791080

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

410534

show subpopulations

African (AFR)

AF:

0.0000699

AC:

AN:

14304

American (AMR)

AF:

0.0000249

AC:

AN:

40238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19252

East Asian (EAS)

AF:

0.00

AC:

AN:

36494

South Asian (SAS)

AF:

0.00

AC:

AN:

67460

European-Finnish (FIN)

AF:

0.0000292

AC:

AN:

34204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2970

European-Non Finnish (NFE)

AF:

0.00000556

AC:

AN:

539176

Other (OTH)

AF:

0.0000270

AC:

AN:

36982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

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

AF:

0.00

AC:

AN:

74826

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35968

African (AFR)

AF:

0.00

AC:

AN:

11194

American (AMR)

AF:

0.00

AC:

AN:

8862

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2026

East Asian (EAS)

AF:

0.00

AC:

AN:

3676

South Asian (SAS)

AF:

0.00

AC:

AN:

2280

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5728

Middle Eastern (MID)

AF:

0.00

AC:

AN:

142

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

39382

Other (OTH)

AF:

0.00

AC:

AN:

998

Alfa

AF:

0.0000617

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Classic homocystinuria (3)

Familial thoracic aortic aneurysm and aortic dissection (1)

Homocystinuria (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.8

PhyloP100

6.8

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.96

MVP

0.95

MPC

1.3

ClinPred

1.0

GERP RS

4.4

Varity_R

0.96

gMVP

0.97

Mutation Taster

=0/100

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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