rs9982015

Variant names:

• chr21-43069982-T-C
• rs9982015
• NM_000071.3:c.210-1367A>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.210-1367A>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 0.0034 (11 hom., cov: 5)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 intron
• Scores: Splicing: ADA: 0.0001699
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• Publications: 7 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.210-1367A>G		intron_variant	Intron 3 of 16	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.210-1367A>G		intron_variant	Intron 3 of 16	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 136 AN: 39548 Hom.: 11 Cov.: 5

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.000828

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0185

Gnomad NFE AF: 0.000247

Gnomad OTH AF: 0.00644

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: 0.00341 AC: 135 AN: 39586 Hom.: 11 Cov.: 5 AF XY: 0.00344 AC XY: 65 AN XY: 18868

African (AFR) AF: 0.0154 AC: 116 AN: 7514

American (AMR) AF: 0.00242 AC: 10 AN: 4136

Ashkenazi Jewish (ASJ) AF: 0.000828 AC: 1 AN: 1208

East Asian (EAS) AF: 0.00 AC: 0 AN: 2542

South Asian (SAS) AF: 0.00 AC: 0 AN: 946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 52

European-Non Finnish (NFE) AF: 0.000247 AC: 5 AN: 20206

Other (OTH) AF: 0.00630 AC: 3 AN: 476

Alfa AF: 0.0277 Hom.: 21

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.091
DANN	Benign	0.45
PhyloP100		-1.5
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.014
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: rs9982015; hg19: chr21-44490092;