rs181472622

Variant names:

• chr21-43065453-C-T
• rs181472622
• NM_000071.3:c.600G>A

Variant summary

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

The NM_000071.3(CBS):​c.600G>A​(p.Pro200Pro) 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).

• Frequency:
  • Genomes: not found (cov: 5)
  • Exomes 𝑓: 0.0000047 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.99
• 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 21-43065453-C-T is Benign according to our data. Variant chr21-43065453-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 340087.
• BP7: Synonymous conserved (PhyloP=-1.99 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000071.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.600G>A	p.Pro200Pro	synonymous	Exon 7 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.600G>A	p.Pro200Pro	synonymous	Exon 7 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.600G>A	p.Pro200Pro	synonymous	Exon 7 of 18	NP_001171480.1	P35520-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.600G>A	p.Pro200Pro	synonymous	Exon 7 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.600G>A	p.Pro200Pro	synonymous	Exon 7 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.600G>A	p.Pro200Pro	synonymous	Exon 7 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD2 exomes AF: 0.000417 AC: 104 AN: 249506 AF XY: 0.000429

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00250

Gnomad NFE exome AF: 0.000401

Gnomad OTH exome AF: 0.000492

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000468 AC: 2 AN: 427724 Hom.: 0 Cov.: 0 AF XY: 0.00000439 AC XY: 1 AN XY: 227706

African (AFR) AF: 0.00 AC: 0 AN: 13374

American (AMR) AF: 0.00 AC: 0 AN: 29294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13950

East Asian (EAS) AF: 0.00 AC: 0 AN: 31278

South Asian (SAS) AF: 0.0000195 AC: 1 AN: 51348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1842

European-Non Finnish (NFE) AF: 0.00000425 AC: 1 AN: 235432

Other (OTH) AF: 0.00 AC: 0 AN: 24124

GnomAD4 genome Cov.: 5

Alfa AF: 0.000181 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	CBS-related disorder (1)
-	1	-	Classic homocystinuria (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.4
DANN	Benign	0.71
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs181472622; hg19: chr21-44485563; COSMIC: COSV100658137; COSMIC: COSV100658137;