dbSNP rs2298758: CBS:p.Asn212Asn (chr21-43065417-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000071.3(CBS):c.636C>T(p.Asn212Asn) 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 Benign (★★).

Frequency

Genomes: 𝑓 0.00073 ( 0 hom., cov: 5)

Exomes 𝑓: 0.0019 ( 68 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.783

Publications

7 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 21-43065417-G-A is Benign according to our data. Variant chr21-43065417-G-A is described in ClinVar as Benign. ClinVar VariationId is 136668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.783 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0019 (850/448074) while in subpopulation EAS AF = 0.0215 (676/31416). AF 95% confidence interval is 0.0202. There are 68 homozygotes in GnomAdExome4. There are 449 alleles in the male GnomAdExome4 subpopulation. Median coverage is 4. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 68 AR gene

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.636C>T	p.Asn212Asn	synonymous	Exon 7 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.636C>T	p.Asn212Asn	synonymous	Exon 7 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.636C>T	p.Asn212Asn	synonymous	Exon 7 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.636C>T	p.Asn212Asn	synonymous	Exon 7 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.636C>T	p.Asn212Asn	synonymous	Exon 7 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.636C>T	p.Asn212Asn	synonymous	Exon 7 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

AF:

0.000731

AC:

AN:

20526

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0146

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00128

AC:

319

AN:

250098

AF XY:

0.00112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0148

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000177

Gnomad OTH exome

AF:

0.000818

GnomAD4 exome

AF:

0.00190

AC:

850

AN:

448074

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

449

AN XY:

239922

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13762

American (AMR)

AF:

0.00

AC:

AN:

30862

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15034

East Asian (EAS)

AF:

0.0215

AC:

676

AN:

31416

South Asian (SAS)

AF:

0.000857

AC:

AN:

56006

European-Finnish (FIN)

AF:

0.0000697

AC:

AN:

28684

Middle Eastern (MID)

AF:

0.000518

AC:

AN:

1930

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

245760

Other (OTH)

AF:

0.00118

AC:

AN:

24620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000729

AC:

AN:

20588

Hom.:

Cov.:

AF XY:

0.000818

AC XY:

AN XY:

9784

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

5086

American (AMR)

AF:

0.00

AC:

AN:

2126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

564

East Asian (EAS)

AF:

0.0146

AC:

AN:

958

South Asian (SAS)

AF:

0.00

AC:

AN:

330

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

9750

Other (OTH)

AF:

0.00

AC:

AN:

228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000233

Hom.:

Asia WGS

AF:

0.00809

AC:

AN:

3476

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Classic homocystinuria (2)

CBS-related disorder (1)

Connective tissue disorder (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.76

(source)

DANN

Benign

0.80

PhyloP100

-0.78

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

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