rs2850144

Positions:

• chr21-43076866-C-G
• chr21-43076866-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.00

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_001320298.2	c.-251G>C		5_prime_UTR_variant	1/18
CBS	XM_047441024.1	c.-251G>C		5_prime_UTR_variant	1/19
CBS	XM_047441025.1	c.-686G>C		5_prime_UTR_variant	1/20
CBS	XM_047441030.1	c.-251G>C		5_prime_UTR_variant	1/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000441030.5	c.-211G>C		5_prime_UTR_variant	1/6	5

Frequencies

GnomAD3 genomes AF: 0.879 AC: 113408 AN: 129004 Hom.: 51920 Cov.: 20

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: 46 AN: 54 Hom.: 20 Cov.: 0 AF XY: 0.857 AC XY: 36 AN XY: 42

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.: 20 AF XY: 0.874 AC XY: 54201 AN XY: 62046

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

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

Other links and lift over

dbSNP: rs2850144; hg19: chr21-44496976;