21-43067923-T-C

Variant names:

• chr21-43067923-T-C
• rs234714
• ENST00000461686.5:n.482A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The ENST00000461686.5(CBS):​n.482A>G variant causes a non coding transcript exon 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 0.000061 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS ENST00000461686.5 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0100
• Publications: 25 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 21-43067923-T-C is Benign according to our data. Variant chr21-43067923-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2674643.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.316+586A>G		intron_variant	Intron 4 of 16	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.316+586A>G		intron_variant	Intron 4 of 16	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes AF: 0.0000613 AC: 3 AN: 48932 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000473

Gnomad SAS AF: 0.000519

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000437

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000129 AC: 7 AN: 54350 Hom.: 0 Cov.: 0 AF XY: 0.0000649 AC XY: 2 AN XY: 30834

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

African (AFR) AF: 0.00 AC: 0 AN: 458

American (AMR) AF: 0.000134 AC: 1 AN: 7436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1224

East Asian (EAS) AF: 0.00 AC: 0 AN: 1350

South Asian (SAS) AF: 0.00 AC: 0 AN: 14060

European-Finnish (FIN) AF: 0.000404 AC: 1 AN: 2474

Middle Eastern (MID) AF: 0.00113 AC: 1 AN: 888

European-Non Finnish (NFE) AF: 0.000166 AC: 4 AN: 24036

Other (OTH) AF: 0.00 AC: 0 AN: 2424

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000613 AC: 3 AN: 48962 Hom.: 0 Cov.: 0 AF XY: 0.0000412 AC XY: 1 AN XY: 24266

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

African (AFR) AF: 0.00 AC: 0 AN: 7556

American (AMR) AF: 0.00 AC: 0 AN: 8012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1336

East Asian (EAS) AF: 0.000475 AC: 1 AN: 2106

South Asian (SAS) AF: 0.000518 AC: 1 AN: 1930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 128

European-Non Finnish (NFE) AF: 0.0000437 AC: 1 AN: 22894

Other (OTH) AF: 0.00 AC: 0 AN: 714

⚠️ 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: 0.762 Hom.: 78248

Asia WGS AF: 0.698 AC: 2428 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Classic homocystinuria Benign:1

Dec 26, 2023

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	6.4
DANN	Benign	0.52
PhyloP100		-0.010
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs234714; hg19: chr21-44488033; COSMIC: COSV61442068; COSMIC: COSV61442068;