rs2851391

Variant names:

• chr21-43067294-T-C
• rs2851391
• NM_000071.3:c.317-917A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000071.3(CBS):​c.317-917A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (2039 hom., cov: 4)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.492
• Publications: 77 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

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.317-917A>G		intron	N/A	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.317-917A>G		intron	N/A	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.317-917A>G		intron	N/A	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.317-917A>G		intron	N/A	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.317-917A>G		intron	N/A	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.317-917A>G		intron	N/A	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 6650 AN: 17990 Hom.: 2036 Cov.: 4

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.391

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.288

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.369 AC: 6651 AN: 18006 Hom.: 2039 Cov.: 4 AF XY: 0.338 AC XY: 2899 AN XY: 8576

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.436 AC: 797 AN: 1826

American (AMR) AF: 0.182 AC: 773 AN: 4244

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 214 AN: 458

East Asian (EAS) AF: 0.552 AC: 713 AN: 1292

South Asian (SAS) AF: 0.356 AC: 288 AN: 808

European-Finnish (FIN) AF: 0.292 AC: 266 AN: 912

Middle Eastern (MID) AF: 0.379 AC: 22 AN: 58

European-Non Finnish (NFE) AF: 0.435 AC: 3494 AN: 8028

Other (OTH) AF: 0.280 AC: 65 AN: 232

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.570 Hom.: 97219

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.0
DANN	Benign	0.27
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2851391; hg19: chr21-44487404; COSMIC: COSV61445871; COSMIC: COSV61445871;