chr21-43058862-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP2PP5_Very_Strong

The NM_000071.3(CBS):c.1330G>A(p.Asp444Asn) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D444D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 0)

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 7.50

Publications

41 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

CBS links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 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.

PP5

Variant 21-43058862-C-T is Pathogenic according to our data. Variant chr21-43058862-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 126.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	UniProt
CBS	NM_000071.3	MANE Select	c.1330G>A	p.Asp444Asn	missense	Exon 14 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.1330G>A	p.Asp444Asn	missense	Exon 14 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.1330G>A	p.Asp444Asn	missense	Exon 14 of 18	NP_001171480.1	P35520-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CBS	ENST00000398165.8	TSL:1 MANE Select	c.1330G>A	p.Asp444Asn	missense	Exon 14 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.1330G>A	p.Asp444Asn	missense	Exon 14 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.1330G>A	p.Asp444Asn	missense	Exon 14 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.000334

AC:

AN:

167900

AF XY:

0.000314

show subpopulations

Gnomad AFR exome

AF:

0.000206

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000250

Gnomad OTH exome

AF:

0.000649

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000360

Hom.:

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000468

AC:

ExAC

AF:

0.000153

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Classic homocystinuria (7)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (2)

not provided (2)

CBS-related disorder (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

Homocystinuria (1)

Homocystinuria, pyridoxine-responsive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.3

PhyloP100

7.5

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.60

Sift

Benign

0.10

Sift4G

Benign

0.14

Polyphen

0.12

Vest4

0.93

MVP

0.90

MPC

0.42

ClinPred

0.14

GERP RS

4.7

PromoterAI

0.0090

Neutral

(source)

Varity_R

0.75

gMVP

0.79

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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