12-26539038-C-T

Variant names:

• chr12-26539038-C-T
• rs4414322
• NM_002223.4:c.5073+11209G>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.5073+11209G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 152,084 control chromosomes in the GnomAD database, including 28,274 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 0.57 (28274 hom., cov: 33)
• Consequence: ITPR2 NM_002223.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.251
• Publications: 4 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR2	NM_002223.4	c.5073+11209G>A		intron_variant	Intron 37 of 56	ENST00000381340.8	NP_002214.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR2	ENST00000381340.8	c.5073+11209G>A		intron_variant	Intron 37 of 56	1	NM_002223.4	ENSP00000370744.3

Frequencies

GnomAD3 genomes AF: 0.566 AC: 86018 AN: 151964 Hom.: 28273 Cov.: 33

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.648

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.737

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.584

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

GnomAD4 genome AF: 0.566 AC: 86033 AN: 152084 Hom.: 28274 Cov.: 33 AF XY: 0.562 AC XY: 41765 AN XY: 74348

African (AFR) AF: 0.257 AC: 10632 AN: 41440

American (AMR) AF: 0.476 AC: 7279 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 2249 AN: 3472

East Asian (EAS) AF: 0.256 AC: 1324 AN: 5176

South Asian (SAS) AF: 0.601 AC: 2900 AN: 4822

European-Finnish (FIN) AF: 0.737 AC: 7800 AN: 10588

Middle Eastern (MID) AF: 0.538 AC: 157 AN: 292

European-Non Finnish (NFE) AF: 0.763 AC: 51857 AN: 67986

Other (OTH) AF: 0.580 AC: 1223 AN: 2110

Alfa AF: 0.647 Hom.: 4428

Bravo AF: 0.530

Asia WGS AF: 0.425 AC: 1480 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.2
DANN	Benign	0.42
PhyloP100		-0.25
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: rs4414322; hg19: chr12-26691971;