rs2254210

chr12-47879931-G-Achr12-47879931-G-Cchr12-47879931-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000376.3(VDR):c.-2-816C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 151,970 control chromosomes in the GnomAD database, including 9,158 homozygotes. 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 0.34 (9158 hom., cov: 31)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.100

Genes affected

VDR (HGNC:12679): (vitamin D receptor) This gene encodes vitamin D3 receptor, which is a member of the nuclear hormone receptor superfamily of ligand-inducible transcription factors. This receptor also functions as a receptor for the secondary bile acid, lithocholic acid. Downstream targets of vitamin D3 receptor are principally involved in mineral metabolism, though this receptor regulates a variety of other metabolic pathways, such as those involved in immune response and cancer. Mutations in this gene are associated with type II vitamin D-resistant rickets. A single nucleotide polymorphism in the initiation codon results in an alternate translation start site three codons downstream. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Jun 2018]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VDR	NM_000376.3	c.-2-816C>T		intron_variant		ENST00000549336.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VDR	ENST00000549336.6	c.-2-816C>T		intron_variant		1	NM_000376.3	P1

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52403 AN: 151854 Hom.: 9161 Cov.: 31

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.340

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.345 AC: 52402 AN: 151970 Hom.: 9158 Cov.: 31 AF XY: 0.343 AC XY: 25491 AN XY: 74284

Gnomad4 AFR AF: 0.331

Gnomad4 AMR AF: 0.284

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.281

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.423

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.336

Alfa AF: 0.346 Hom.: 13917

Bravo AF: 0.337

Asia WGS AF: 0.214 AC: 745 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	1.5
Dann	Benign	0.41

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: rs2254210; hg19: chr12-48273714;