12-26706463-G-T

Variant names:

• chr12-26706463-G-T
• rs3782309
• NM_002223.4:c.951+4710C>A

Variant summary

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

The NM_002223.4(ITPR2):​c.951+4710C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0823 in 152,010 control chromosomes in the GnomAD database, including 677 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 0.082 (677 hom., cov: 32)
• Consequence: ITPR2 NM_002223.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.513
• Publications: 8 publications found

Genes affected

ITPR2 (HGNC:6181): (inositol 1,4,5-trisphosphate receptor type 2) The protein encoded by this gene belongs to the inositol 1,4,5-triphosphate receptor family, whose members are second messenger intracellular calcium release channels. These proteins mediate a rise in cytoplasmic calcium in response to receptor activated production of inositol triphosphate. Inositol triphosphate receptor-mediated signaling is involved in many processes including cell migration, cell division, smooth muscle contraction, and neuronal signaling. This protein is a type 2 receptor that consists of a cytoplasmic amino-terminus that binds inositol triphosphate, six membrane-spanning helices that contribute to the ion pore, and a short cytoplasmic carboxy-terminus. A mutation in this gene has been associated with anhidrosis, suggesting that intracellular calcium release mediated by this protein is required for eccrine sweat production. [provided by RefSeq, Apr 2015]

ITPR2 Gene-Disease associations (from GenCC):

• isolated anhidrosis with normal sweat glands

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR2	NM_002223.4	c.951+4710C>A		intron_variant	Intron 9 of 56	ENST00000381340.8	NP_002214.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR2	ENST00000381340.8	c.951+4710C>A		intron_variant	Intron 9 of 56	1	NM_002223.4	ENSP00000370744.3
ITPR2	ENST00000540791.1	n.526+4710C>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0824 AC: 12509 AN: 151892 Hom.: 676 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0835

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.0336

Gnomad SAS AF: 0.0352

Gnomad FIN AF: 0.0500

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.0881

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

GnomAD4 genome AF: 0.0823 AC: 12511 AN: 152010 Hom.: 677 Cov.: 32 AF XY: 0.0769 AC XY: 5715 AN XY: 74298

African (AFR) AF: 0.0249 AC: 1032 AN: 41442

American (AMR) AF: 0.0834 AC: 1273 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 270 AN: 3472

East Asian (EAS) AF: 0.0338 AC: 175 AN: 5174

South Asian (SAS) AF: 0.0348 AC: 167 AN: 4802

European-Finnish (FIN) AF: 0.0500 AC: 528 AN: 10560

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.130 AC: 8836 AN: 67978

Other (OTH) AF: 0.0877 AC: 185 AN: 2110

Alfa AF: 0.112 Hom.: 1992

Bravo AF: 0.0842

Asia WGS AF: 0.0370 AC: 128 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.73
DANN	Benign	0.53
PhyloP100		-0.51
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: rs3782309; hg19: chr12-26859396;