chr21-43067781-G-A

Variant names:

• chr21-43067781-G-A
• rs234713
• ENST00000461686.5:n.624C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The ENST00000461686.5(CBS):​n.624C>T variant causes a non coding transcript exon 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: not found (cov: 14)
• Consequence: CBS ENST00000461686.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.242
• Publications: 18 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-43067781-G-A is Benign according to our data. Variant chr21-43067781-G-A is described in ClinVar as Benign. ClinVar VariationId is 3895029.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000461686.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.316+728C>T		intron	N/A	NP_000062.1
	CBS	NM_001321072.1		c.-3C>T		5_prime_UTR	Exon 1 of 14	NP_001308001.1
	CBS	NM_001178008.3		c.316+728C>T		intron	N/A	NP_001171479.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000461686.5	TSL:1	n.624C>T		non_coding_transcript_exon	Exon 1 of 14
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.316+728C>T		intron	N/A	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.316+728C>T		intron	N/A	ENSP00000344460.5

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD2 exomes AF: 0.253 AC: 33925 AN: 134230 AF XY: 0.259

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.0272

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.328

Gnomad OTH exome AF: 0.265

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 14

Alfa AF: 0.301 Hom.: 1651

Asia WGS AF: 0.137 AC: 478 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs234713; hg19: chr21-44487891;