dbSNP rs2850144: CBS:c.-251G>C (chr21-43076866-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001320298.2(CBS):c.-251G>C variant causes a 5 prime UTR 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 0.88 ( 51950 hom., cov: 20)

Exomes 𝑓: 0.85 ( 20 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_001320298.2 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.00

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 21-43076866-C-G is Benign according to our data. Variant chr21-43076866-C-G is described in ClinVar as [Benign]. Clinvar id is 1168575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
CBS	NM_001320298.2 link	c.-251G>C	5_prime_UTR_variant	Exon 1 of 18	NP_001307227.1	P35520-1B7Z2D6
CBS	XM_047441024.1 link	c.-251G>C	5_prime_UTR_variant	Exon 1 of 19	XP_047296980.1
CBS	XM_047441025.1 link	c.-686G>C	5_prime_UTR_variant	Exon 1 of 20	XP_047296981.1
CBS	XM_047441030.1 link	c.-251G>C	5_prime_UTR_variant	Exon 1 of 19	XP_047296986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000441030.5 link	c.-211G>C		5_prime_UTR_variant	Exon 1 of 6	5		ENSP00000388235.1		C9JMA6

Frequencies

GnomAD3 genomes

AF:

0.879

AC:

113408

AN:

129004

Hom.:

51920

Cov.:

show subpopulations

Gnomad AFR

AF:

0.847

Gnomad AMI

AF:

0.869

Gnomad AMR

AF:

0.717

Gnomad ASJ

AF:

0.895

Gnomad EAS

AF:

0.881

Gnomad SAS

AF:

0.873

Gnomad FIN

AF:

0.906

Gnomad MID

AF:

0.893

Gnomad NFE

AF:

0.934

Gnomad OTH

AF:

0.883

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.852

AC:

AN:

Hom.:

Cov.:

AF XY:

0.857

AC XY:

AN XY:

show subpopulations

Gnomad4 EAS exome

AF:

0.667

Gnomad4 SAS exome

AF:

0.500

Gnomad4 FIN exome

AF:

0.500

Gnomad4 NFE exome

AF:

0.905

Gnomad4 OTH exome

AF:

1.00

GnomAD4 genome

AF:

0.879

AC:

113479

AN:

129092

Hom.:

51950

Cov.:

AF XY:

0.874

AC XY:

54201

AN XY:

62046

show subpopulations

Gnomad4 AFR

AF:

0.847

Gnomad4 AMR

AF:

0.716

Gnomad4 ASJ

AF:

0.895

Gnomad4 EAS

AF:

0.881

Gnomad4 SAS

AF:

0.873

Gnomad4 FIN

AF:

0.906

Gnomad4 NFE

AF:

0.934

Gnomad4 OTH

AF:

0.884

Alfa

AF:

0.656

Hom.:

1546

Asia WGS

AF:

0.666

AC:

2313

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.90

DANN

Benign

0.45

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over