chr21-43066348-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PP2PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):c.346G>A(p.Gly116Arg) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G116G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 8)

Exomes 𝑓: 0.0000078 ( 1 hom. )

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.84

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: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000071.3

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, 0.99

PP5

Variant 21-43066348-C-T is Pathogenic according to our data. Variant chr21-43066348-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 188787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.346G>A	p.Gly116Arg	missense_variant	Exon 5 of 17	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.346G>A	p.Gly116Arg	missense_variant	Exon 5 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251070

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000779

AC:

AN:

769730

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

398984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

14244

American (AMR)

AF:

0.0000772

AC:

AN:

38882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19008

East Asian (EAS)

AF:

0.0000279

AC:

AN:

35818

South Asian (SAS)

AF:

0.00

AC:

AN:

66696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2796

European-Non Finnish (NFE)

AF:

0.00000383

AC:

AN:

522786

Other (OTH)

AF:

0.00

AC:

AN:

36258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

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

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:3

Feb 23, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 19, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 16, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 116 of the CBS protein (p.Gly116Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with homocystinuria (PMID: 25455305, 29508359). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188787). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 20066033). For these reasons, this variant has been classified as Pathogenic. -

Homocystinuria

Pathogenic:1

Feb 27, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CBS c.346G>A (p.Gly116Arg) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251070 control chromosomes. c.346G>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Homocystinuria (example, Suri_2014, Chen_1999). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Singh_CBS_PLoSGenetics_2010). The most pronounced variant effect results in complete absence of normal cystathionine beta-synthase (CBS) enzyme activity in a yeast in-vitro system. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D;D;D;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.99

.;.;.;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;H;H;H;.

PhyloP100

6.8

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-8.0

D;D;D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

1.0

MutPred

0.96

Gain of MoRF binding (P = 0.0239);Gain of MoRF binding (P = 0.0239);Gain of MoRF binding (P = 0.0239);Gain of MoRF binding (P = 0.0239);Gain of MoRF binding (P = 0.0239);

MVP

0.94

MPC

1.2

ClinPred

1.0

GERP RS

5.4

Varity_R

0.95

gMVP

0.97

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: -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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over