dbSNP rs201158177: CBS:c.1145+7C>T (chr21-43060434-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_000071.3(CBS):c.1145+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0051 ( 3 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 splice_region, intron

Scores

Splicing: ADA: 0.0002891

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.961

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

CBS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 21-43060434-G-A is Benign according to our data. Variant chr21-43060434-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00505 (99/19600) while in subpopulation MID AF = 0.0125 (1/80). AF 95% confidence interval is 0.0062. There are 3 homozygotes in GnomAdExome4. There are 47 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

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	Effect	Exon Rank	Protein	UniProt
CBS	NM_000071.3	MANE Select	c.1145+7C>T	splice_region intron	N/A	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.1145+7C>T	splice_region intron	N/A	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.1145+7C>T	splice_region intron	N/A	NP_001171480.1	P35520-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CBS	ENST00000398165.8	TSL:1 MANE Select	c.1145+7C>T	splice_region intron	N/A	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.1145+7C>T	splice_region intron	N/A	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.1145+7C>T	splice_region intron	N/A	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

AF:

0.00310

AC:

AN:

968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

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:

0.00937

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00606

AC:

1512

AN:

249694

AF XY:

0.00616

show subpopulations

Gnomad AFR exome

AF:

0.000619

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0279

Gnomad NFE exome

AF:

0.00698

Gnomad OTH exome

AF:

0.00458

GnomAD4 exome

AF:

0.00505

AC:

AN:

19600

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

AN XY:

10886

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

710

American (AMR)

AF:

0.00121

AC:

AN:

1656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

418

East Asian (EAS)

AF:

0.00

AC:

AN:

630

South Asian (SAS)

AF:

0.000247

AC:

AN:

4046

European-Finnish (FIN)

AF:

0.0241

AC:

AN:

582

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00754

AC:

AN:

10480

Other (OTH)

AF:

0.00200

AC:

AN:

998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.00308

AC:

AN:

974

Hom.:

Cov.:

AF XY:

0.00607

AC XY:

AN XY:

494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

230

American (AMR)

AF:

0.00

AC:

AN:

200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00943

AC:

AN:

318

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.00628

Hom.:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00578

EpiControl

AF:

0.00522

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (5)

Classic homocystinuria (2)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.28

(source)

DANN

Benign

0.37

PhyloP100

-0.96

PromoterAI

0.0028

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00029

dbscSNV1_RF

Benign

0.0020

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