rs189362155

Variant names:

• chr21-43065673-C-G
• rs189362155
• NM_000071.3:c.474G>C

Your query was ambiguous. Multiple possible variants found:

• chr21-43065673-C-G
• chr21-43065673-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The ENST00000398165.8(CBS):​c.474G>C​(p.Ala158Ala) 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A158A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS ENST00000398165.8 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -6.66
• Publications: 0 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=-0.86).
• BP6: Variant 21-43065673-C-G is Benign according to our data. Variant chr21-43065673-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1693768.
• BP7: Synonymous conserved (PhyloP=-6.66 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000398165.8. 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.474G>C	p.Ala158Ala	synonymous	Exon 6 of 17	NP_000062.1
	CBS	NM_001178008.3		c.474G>C	p.Ala158Ala	synonymous	Exon 6 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.474G>C	p.Ala158Ala	synonymous	Exon 6 of 18	NP_001171480.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.474G>C	p.Ala158Ala	synonymous	Exon 6 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.474G>C	p.Ala158Ala	synonymous	Exon 6 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.474G>C	p.Ala158Ala	synonymous	Exon 6 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.034
DANN	Benign	0.35
PhyloP100		-6.7

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

Other links and lift over

dbSNP: rs189362155; hg19: chr21-44485783;