rs1005584

Positions:

• chr21-43056985-C-T
• chr21-43056985-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000071.3(CBS):​c.1468-98G>A variant causes a intron 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 0.075 (49 hom., cov: 3)
  • Exomes 𝑓: 0.0032 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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]

CBS (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP6: Variant 21-43056985-C-T is Benign according to our data. Variant chr21-43056985-C-T is described in ClinVar as [Benign]. Clinvar id is 1235563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.1468-98G>A		intron_variant		ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1468-98G>A		intron_variant		1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 453 AN: 6124 Hom.: 48 Cov.: 3 FAILED QC

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.0500

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0147

Gnomad MID AF: 0.0270

Gnomad NFE AF: 0.0556

Gnomad OTH AF: 0.0887

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00320 AC: 67 AN: 20970 Hom.: 2 AF XY: 0.00338 AC XY: 39 AN XY: 11552

Gnomad4 AFR exome AF: 0.0233

Gnomad4 AMR exome AF: 0.00330

Gnomad4 ASJ exome AF: 0.00224

Gnomad4 EAS exome AF: 0.000729

Gnomad4 SAS exome AF: 0.00541

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00236

Gnomad4 OTH exome AF: 0.00183

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0748 AC: 458 AN: 6124 Hom.: 49 Cov.: 3 AF XY: 0.0708 AC XY: 205 AN XY: 2894

Gnomad4 AFR AF: 0.253

Gnomad4 AMR AF: 0.0260

Gnomad4 ASJ AF: 0.0403

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.0147

Gnomad4 NFE AF: 0.0557

Gnomad4 OTH AF: 0.0794

Alfa AF: 0.0500 Hom.: 320

Asia WGS AF: 0.0950 AC: 332 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	19
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.53		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1005584; hg19: chr21-44477095;