rs1788484

Variant names:

• chr21-43076831-C-T
• rs1788484
• NM_001320298.2:c.-216G>A

Variant summary

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

The NM_001320298.2(CBS):​c.-216G>A variant causes a 5 prime UTR 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 0.000022 (0 hom., cov: 17)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_001320298.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 20 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=-0.77).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_001320298.2	c.-216G>A		5_prime_UTR_variant	Exon 1 of 18		NP_001307227.1
CBS	XM_047441024.1	c.-216G>A		5_prime_UTR_variant	Exon 1 of 19		XP_047296980.1
CBS	XM_047441025.1	c.-651G>A		5_prime_UTR_variant	Exon 1 of 20		XP_047296981.1
CBS	XM_047441030.1	c.-216G>A		5_prime_UTR_variant	Exon 1 of 19		XP_047296986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000441030.5	c.-176G>A		5_prime_UTR_variant	Exon 1 of 6	5		ENSP00000388235.1

Frequencies

GnomAD3 genomes AF: 0.0000221 AC: 3 AN: 135672 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.0000498

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000126

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000221 AC: 3 AN: 135772 Hom.: 0 Cov.: 17 AF XY: 0.0000152 AC XY: 1 AN XY: 65670

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

African (AFR) AF: 0.0000497 AC: 2 AN: 40276

American (AMR) AF: 0.00 AC: 0 AN: 13552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3138

East Asian (EAS) AF: 0.00 AC: 0 AN: 4486

South Asian (SAS) AF: 0.00 AC: 0 AN: 4072

European-Finnish (FIN) AF: 0.000126 AC: 1 AN: 7968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59432

Other (OTH) AF: 0.00 AC: 0 AN: 1880

⚠️ 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: 0.269 Hom.: 11508

Asia WGS AF: 0.227 AC: 793 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.9
DANN	Benign	0.93
PhyloP100		-1.1
PromoterAI		0.14	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1788484; hg19: chr21-44496941; COSMIC: COSV61445152;