NM_002223.4:c.4482C>T

Variant names:

• chr12-26580054-G-A
• rs2230376
• NM_002223.4:c.4482C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002223.4(ITPR2):​c.4482C>T​(p.Pro1494Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,608,224 control chromosomes in the GnomAD database, including 76,962 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 0.25 (5419 hom., cov: 32)
  • Exomes 𝑓: 0.31 (71543 hom.)
• Consequence: ITPR2 NM_002223.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.82
• Publications: 14 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP7: Synonymous conserved (PhyloP=-3.82 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002223.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR2	NM_002223.4	MANE Select	c.4482C>T	p.Pro1494Pro	synonymous	Exon 33 of 57	NP_002214.2
	ITPR2	NM_001414174.1		c.4479C>T	p.Pro1493Pro	synonymous	Exon 33 of 57	NP_001401103.1
	ITPR2	NM_001414175.1		c.4482C>T	p.Pro1494Pro	synonymous	Exon 33 of 55	NP_001401104.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR2	ENST00000381340.8	TSL:1 MANE Select	c.4482C>T	p.Pro1494Pro	synonymous	Exon 33 of 57	ENSP00000370744.3

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38288 AN: 151976 Hom.: 5417 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.0830

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.266

GnomAD2 exomes AF: 0.269 AC: 66620 AN: 247824 AF XY: 0.274

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.0891

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.295

GnomAD4 exome AF: 0.306 AC: 446290 AN: 1456130 Hom.: 71543 Cov.: 30 AF XY: 0.305 AC XY: 221174 AN XY: 724526

African (AFR) AF: 0.118 AC: 3944 AN: 33398

American (AMR) AF: 0.213 AC: 9476 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6335 AN: 26074

East Asian (EAS) AF: 0.0783 AC: 3100 AN: 39614

South Asian (SAS) AF: 0.247 AC: 21240 AN: 85870

European-Finnish (FIN) AF: 0.355 AC: 18915 AN: 53246

Middle Eastern (MID) AF: 0.255 AC: 1460 AN: 5722

European-Non Finnish (NFE) AF: 0.329 AC: 364262 AN: 1107432

Other (OTH) AF: 0.292 AC: 17558 AN: 60196

GnomAD4 genome AF: 0.252 AC: 38311 AN: 152094 Hom.: 5419 Cov.: 32 AF XY: 0.252 AC XY: 18712 AN XY: 74330

African (AFR) AF: 0.127 AC: 5273 AN: 41508

American (AMR) AF: 0.250 AC: 3820 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 802 AN: 3464

East Asian (EAS) AF: 0.0830 AC: 430 AN: 5180

South Asian (SAS) AF: 0.259 AC: 1249 AN: 4824

European-Finnish (FIN) AF: 0.353 AC: 3727 AN: 10568

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.325 AC: 22058 AN: 67968

Other (OTH) AF: 0.267 AC: 566 AN: 2116

Alfa AF: 0.299 Hom.: 31107

Bravo AF: 0.239

Asia WGS AF: 0.207 AC: 721 AN: 3476

EpiCase AF: 0.321

EpiControl AF: 0.317

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.14
DANN	Benign	0.32
PhyloP100		-3.8
Mutation Taster		=83/17	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: rs2230376; hg19: chr12-26732987; COSMIC: COSV67270211;