21-43065441-C-G

Variant names:

• chr21-43065441-C-G
• rs539670390
• NM_000071.3:c.612G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000071.3(CBS):​c.612G>C​(p.Val204Val) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V204V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 5)
  • Exomes 𝑓: 0.000021 (1 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: -1.01
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 21-43065441-C-G is Benign according to our data. Variant chr21-43065441-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 264320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.01 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.612G>C	p.Val204Val	synonymous	Exon 7 of 17	NP_000062.1
	CBS	NM_001178008.3		c.612G>C	p.Val204Val	synonymous	Exon 7 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.612G>C	p.Val204Val	synonymous	Exon 7 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.612G>C	p.Val204Val	synonymous	Exon 7 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.612G>C	p.Val204Val	synonymous	Exon 7 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.612G>C	p.Val204Val	synonymous	Exon 7 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes AF: 0.000102 AC: 2 AN: 19692 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000320 AC: 8 AN: 249874 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000622

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000206 AC: 9 AN: 436230 Hom.: 1 Cov.: 0 AF XY: 0.00000860 AC XY: 2 AN XY: 232660

African (AFR) AF: 0.000147 AC: 2 AN: 13626

American (AMR) AF: 0.0000327 AC: 1 AN: 30538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14584

East Asian (EAS) AF: 0.00 AC: 0 AN: 31332

South Asian (SAS) AF: 0.00 AC: 0 AN: 53412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1888

European-Non Finnish (NFE) AF: 0.0000251 AC: 6 AN: 238708

Other (OTH) AF: 0.00 AC: 0 AN: 24432

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000102 AC: 2 AN: 19692 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 9276

African (AFR) AF: 0.00 AC: 0 AN: 4794

American (AMR) AF: 0.00 AC: 0 AN: 2118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 540

East Asian (EAS) AF: 0.00 AC: 0 AN: 1016

South Asian (SAS) AF: 0.00 AC: 0 AN: 364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 34

European-Non Finnish (NFE) AF: 0.000221 AC: 2 AN: 9038

Other (OTH) AF: 0.00 AC: 0 AN: 198

Alfa AF: 0.0000161 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.8
DANN	Benign	0.62
PhyloP100		-1.0

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: rs539670390; hg19: chr21-44485551;