21-43056870-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6_Very_StrongBP7

The NM_000071.3(CBS):c.1485G>A(p.Thr495Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.000031 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.979

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

CBS links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000071.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.205).

BP6

Variant 21-43056870-C-T is Benign according to our data. Variant chr21-43056870-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 471360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.979 with no splicing effect.

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.1485G>A	p.Thr495Thr	synonymous	Exon 16 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.1485G>A	p.Thr495Thr	synonymous	Exon 16 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.1485G>A	p.Thr495Thr	synonymous	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.1485G>A	p.Thr495Thr	synonymous	Exon 16 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.1485G>A	p.Thr495Thr	synonymous	Exon 16 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.1485G>A	p.Thr495Thr	synonymous	Exon 16 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000498

AC:

AN:

160758

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.000219

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000133

Gnomad NFE exome

AF:

0.0000471

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000306

AC:

AN:

163136

Hom.:

Cov.:

AF XY:

0.0000339

AC XY:

AN XY:

88442

show subpopulations

African (AFR)

AF:

0.000210

AC:

AN:

4762

American (AMR)

AF:

0.00

AC:

AN:

12794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3750

East Asian (EAS)

AF:

0.00

AC:

AN:

10678

South Asian (SAS)

AF:

0.00

AC:

AN:

32474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6942

Middle Eastern (MID)

AF:

0.00

AC:

AN:

658

European-Non Finnish (NFE)

AF:

0.0000483

AC:

AN:

82900

Other (OTH)

AF:

0.00

AC:

AN:

8178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

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.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial thoracic aortic aneurysm and aortic dissection (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.093

(source)

DANN

Benign

0.66

PhyloP100

-0.98

Mutation Taster

=100/0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over