Genetic Variant CBS:p.Gln517His (chr21-43056804-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000071.3(CBS):c.1551G>C(p.Gln517His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q517Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 0)

Consequence

CBS
NM_000071.3 missense, splice_region

Scores

Splicing: ADA: 0.0001960

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.543

Publications

0 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: Uncertain_significance. The variant received 1 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.

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.1551G>C	p.Gln517His	missense splice_region	Exon 16 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.1551G>C	p.Gln517His	missense splice_region	Exon 16 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.1551G>C	p.Gln517His	missense splice_region	Exon 16 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.1551G>C	p.Gln517His	missense splice_region	Exon 16 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.1551G>C	p.Gln517His	missense splice_region	Exon 16 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.1551G>C	p.Gln517His	missense splice_region	Exon 16 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

156084

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000114

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.63

Eigen

Benign

0.13

Eigen_PC

Benign

-0.0059

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.74

MetaSVM

Benign

-0.42

MutationAssessor

Pathogenic

3.0

PhyloP100

-0.54

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.8

REVEL

Pathogenic

0.67

Sift

Benign

0.034

Sift4G

Benign

0.10

Polyphen

0.027

Vest4

0.83

MutPred

0.44

Loss of sheet (P = 0.0084)

MVP

0.87

MPC

0.40

ClinPred

0.94

GERP RS

2.9

Varity_R

0.12

gMVP

0.76

Mutation Taster

=52/48

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

dbscSNV1_RF

Benign

0.098

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