chr21-43065231-G-C

Variant names:

• chr21-43065231-G-C
• rs748495689
• NM_000071.3:c.708C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_000071.3(CBS):​c.708C>G​(p.Thr236Thr) variant causes a synonymous 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. Synonymous variant affecting the same amino acid position (i.e. T236T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 0.0000015 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.921
• Publications: 2 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP7: Synonymous conserved (PhyloP=-0.921 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.708C>G	p.Thr236Thr	synonymous_variant	Exon 8 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.708C>G	p.Thr236Thr	synonymous_variant	Exon 8 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251422 AF XY: 0.00000736

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000155 AC: 2 AN: 1292072 Hom.: 1 Cov.: 28 AF XY: 0.00000311 AC XY: 2 AN XY: 643842

African (AFR) AF: 0.00 AC: 0 AN: 31664

American (AMR) AF: 0.00 AC: 0 AN: 42970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000249 AC: 2 AN: 80374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5200

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 965712

Other (OTH) AF: 0.00 AC: 0 AN: 54338

GnomAD4 genome Cov.: 16

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.64
DANN	Benign	0.39
PhyloP100		-0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs748495689; hg19: chr21-44485341;