rs2248098

Variant names:

• chr12-47859573-A-G
• rs2248098
• NM_000376.3:c.278-1885T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-47859573-A-G
• chr12-47859573-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000376.3(VDR):​c.278-1885T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 151,912 control chromosomes in the GnomAD database, including 18,901 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 0.50 (18901 hom., cov: 32)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.372
• Publications: 46 publications found

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]

VDR Gene-Disease associations (from GenCC):

• vitamin D-dependent rickets, type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• vitamin D-dependent rickets, type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.278-1885T>C		intron_variant	Intron 4 of 9	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.278-1885T>C		intron_variant	Intron 4 of 9	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.496 AC: 75324 AN: 151794 Hom.: 18881 Cov.: 32

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.541

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.506

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

GnomAD4 genome AF: 0.496 AC: 75383 AN: 151912 Hom.: 18901 Cov.: 32 AF XY: 0.496 AC XY: 36813 AN XY: 74238

African (AFR) AF: 0.494 AC: 20447 AN: 41410

American (AMR) AF: 0.465 AC: 7113 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1750 AN: 3466

East Asian (EAS) AF: 0.318 AC: 1643 AN: 5164

South Asian (SAS) AF: 0.475 AC: 2290 AN: 4816

European-Finnish (FIN) AF: 0.541 AC: 5713 AN: 10552

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34709 AN: 67910

Other (OTH) AF: 0.507 AC: 1068 AN: 2108

Alfa AF: 0.505 Hom.: 20066

Bravo AF: 0.488

Asia WGS AF: 0.445 AC: 1548 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.66
DANN	Benign	0.46
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

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: rs2248098; hg19: chr12-48253356;