NM_000071.3:c.612G>A

Variant names:

• chr21-43065441-C-T
• rs539670390
• NM_000071.3:c.612G>A
• CBS p.Val204Val

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_000071.3(CBS):​c.612G>A​(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: not found (cov: 5)
  • Exomes 𝑓: 0.0000092 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: ClinGen, Genomics England PanelApp, Orphanet, Myriad Women's Health, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 21-43065441-C-T is Benign according to our data. Variant chr21-43065441-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1607700.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.612G>A	p.Val204Val	synonymous	Exon 7 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.612G>A	p.Val204Val	synonymous	Exon 7 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.612G>A	p.Val204Val	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.612G>A	p.Val204Val	synonymous	Exon 7 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.612G>A	p.Val204Val	synonymous	Exon 7 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.612G>A	p.Val204Val	synonymous	Exon 7 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 249874 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000917 AC: 4 AN: 436230 Hom.: 1 Cov.: 0 AF XY: 0.00000430 AC XY: 1 AN XY: 232660

African (AFR) AF: 0.00 AC: 0 AN: 13626

American (AMR) AF: 0.00 AC: 0 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: 0.0000126 AC: 3 AN: 238708

Other (OTH) AF: 0.0000409 AC: 1 AN: 24432

GnomAD4 genome Cov.: 5

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.6
DANN	Benign	0.65
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs539670390;

hg19: chr21-44485551;