21-43065428-G-T

Variant names:

• chr21-43065428-G-T
• rs137939628
• NM_000071.3:c.625C>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000071.3(CBS):​c.625C>A​(p.Arg209Arg) 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000050 (0 hom., cov: 5)
  • Exomes 𝑓: 0.00031 (33 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.69
• Publications: 2 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 21-43065428-G-T is Benign according to our data. Variant chr21-43065428-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 413349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.69 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 33 AR gene

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.625C>A	p.Arg209Arg	synonymous	Exon 7 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.625C>A	p.Arg209Arg	synonymous	Exon 7 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.625C>A	p.Arg209Arg	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.625C>A	p.Arg209Arg	synonymous	Exon 7 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.625C>A	p.Arg209Arg	synonymous	Exon 7 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.625C>A	p.Arg209Arg	synonymous	Exon 7 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.0000502 AC: 1 AN: 19916 Hom.: 0 Cov.: 5

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00292

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000232 AC: 58 AN: 249820 AF XY: 0.000281

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000312 AC: 137 AN: 439794 Hom.: 33 Cov.: 3 AF XY: 0.000357 AC XY: 84 AN XY: 235096

African (AFR) AF: 0.0000733 AC: 1 AN: 13638

American (AMR) AF: 0.0000650 AC: 2 AN: 30778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14754

East Asian (EAS) AF: 0.00 AC: 0 AN: 31300

South Asian (SAS) AF: 0.00130 AC: 71 AN: 54538

European-Finnish (FIN) AF: 0.000466 AC: 13 AN: 27894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1892

European-Non Finnish (NFE) AF: 0.000200 AC: 48 AN: 240600

Other (OTH) AF: 0.0000820 AC: 2 AN: 24400

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000502 AC: 1 AN: 19916 Hom.: 0 Cov.: 5 AF XY: 0.000106 AC XY: 1 AN XY: 9444

African (AFR) AF: 0.00 AC: 0 AN: 4870

American (AMR) AF: 0.00 AC: 0 AN: 2096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 546

East Asian (EAS) AF: 0.00 AC: 0 AN: 984

South Asian (SAS) AF: 0.00292 AC: 1 AN: 342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 36

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 9322

Other (OTH) AF: 0.00 AC: 0 AN: 206

Alfa AF: 0.000143 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	CBS-related disorder (1)
-	-	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	-0.48
CADD	Benign	9.1
DANN	Benign	0.63
PhyloP100		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137939628; hg19: chr21-44485538;