dbSNP rs367962613: CBS:p.Glu451Asp (chr21-43058839-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate

The NM_000071.3(CBS):c.1353G>C(p.Glu451Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 0)

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.00

Publications

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

CBS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.18509325).

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.1353G>C	p.Glu451Asp	missense	Exon 14 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.1353G>C	p.Glu451Asp	missense	Exon 14 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.1353G>C	p.Glu451Asp	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.1353G>C	p.Glu451Asp	missense	Exon 14 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.1353G>C	p.Glu451Asp	missense	Exon 14 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.1353G>C	p.Glu451Asp	missense	Exon 14 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000607

AC:

AN:

164752

AF XY:

0.00

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:

0.0000151

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00000862

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Classic homocystinuria (2)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Benign

-0.21

CADD

Benign

1.8

(source)

DANN

Benign

0.93

DEOGEN2

Pathogenic

0.82

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.064

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.4

PhyloP100

-1.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.31

Sift

Benign

0.22

Sift4G

Benign

0.27

Polyphen

0.0060

Vest4

0.31

MutPred

0.56

Loss of sheet (P = 0.1398)

MVP

0.40

MPC

0.33

ClinPred

0.081

GERP RS

-5.5

PromoterAI

-0.0050

Neutral

(source)

Varity_R

0.35

gMVP

0.37

Mutation Taster

=64/36

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over