Genetic Variant CBS:p.Glu128Glu (chr21-43066310-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_Very_StrongBP7BS2_Supporting

The NM_000071.3(CBS):c.384G>A(p.Glu128Glu) 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: 𝑓 0.000022 ( 0 hom., cov: 12)

Exomes 𝑓: 0.000020 ( 3 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: 0.389

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 21-43066310-C-T is Benign according to our data. Variant chr21-43066310-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 538701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.389 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.384G>A	p.Glu128Glu	synonymous	Exon 5 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.384G>A	p.Glu128Glu	synonymous	Exon 5 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.384G>A	p.Glu128Glu	synonymous	Exon 5 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.384G>A	p.Glu128Glu	synonymous	Exon 5 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.384G>A	p.Glu128Glu	synonymous	Exon 5 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.384G>A	p.Glu128Glu	synonymous	Exon 5 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

AF:

0.0000221

AC:

AN:

90440

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251054

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000200

AC:

AN:

900284

Hom.:

Cov.:

AF XY:

0.0000173

AC XY:

AN XY:

463522

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15316

American (AMR)

AF:

0.0000240

AC:

AN:

41580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20114

East Asian (EAS)

AF:

0.000107

AC:

AN:

37524

South Asian (SAS)

AF:

0.00

AC:

AN:

69962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3430

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

635636

Other (OTH)

AF:

0.000319

AC:

AN:

40718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000221

AC:

AN:

90440

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

43828

show subpopulations

African (AFR)

AF:

0.000135

AC:

AN:

14838

American (AMR)

AF:

0.00

AC:

AN:

10510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2396

East Asian (EAS)

AF:

0.00

AC:

AN:

4210

South Asian (SAS)

AF:

0.00

AC:

AN:

2922

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

178

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

46472

Other (OTH)

AF:

0.00

AC:

AN:

1232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000153

Hom.:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

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

-0.42

CADD

Benign

9.3

(source)

DANN

Benign

0.93

PhyloP100

0.39

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over