chr21-43055604-T-C

Variant names:

• chr21-43055604-T-C
• rs2124459
• NM_000071.3:c.1552+1199A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000071.3(CBS):​c.1552+1199A>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 0.36 (3017 hom., cov: 6)
  • Exomes 𝑓: 0.61 (173 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.68

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.1552+1199A>G		intron_variant	Intron 16 of 16	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1552+1199A>G		intron_variant	Intron 16 of 16	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 12933 AN: 35840 Hom.: 3015 Cov.: 6 FAILED QC

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.609

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.288

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.606 AC: 538 AN: 888 Hom.: 173 Cov.: 0 AF XY: 0.607 AC XY: 273 AN XY: 450

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.605

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.360 AC: 12946 AN: 35918 Hom.: 3017 Cov.: 6 AF XY: 0.358 AC XY: 5896 AN XY: 16452

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.210

Gnomad4 ASJ AF: 0.394

Gnomad4 EAS AF: 0.608

Gnomad4 SAS AF: 0.337

Gnomad4 FIN AF: 0.546

Gnomad4 NFE AF: 0.430

Gnomad4 OTH AF: 0.289

Alfa AF: 0.394 Hom.: 2532

Asia WGS AF: 0.518 AC: 1802 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.83
DANN	Benign	0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs2124459; hg19: chr21-44475714;