NM_002223.4:c.4630+3131T>C

Variant names:

• chr12-26575582-A-G
• rs16931011
• NM_002223.4:c.4630+3131T>C

Variant summary

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

The NM_002223.4(ITPR2):​c.4630+3131T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 151,958 control chromosomes in the GnomAD database, including 3,271 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 0.20 (3271 hom., cov: 29)
• Consequence: ITPR2 NM_002223.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.217
• Publications: 3 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR2	NM_002223.4	c.4630+3131T>C		intron_variant	Intron 34 of 56	ENST00000381340.8	NP_002214.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR2	ENST00000381340.8	c.4630+3131T>C		intron_variant	Intron 34 of 56	1	NM_002223.4	ENSP00000370744.3

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29760 AN: 151842 Hom.: 3259 Cov.: 29

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.0600

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.212

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

GnomAD4 genome AF: 0.196 AC: 29807 AN: 151958 Hom.: 3271 Cov.: 29 AF XY: 0.193 AC XY: 14336 AN XY: 74272

African (AFR) AF: 0.273 AC: 11289 AN: 41386

American (AMR) AF: 0.154 AC: 2348 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 815 AN: 3470

East Asian (EAS) AF: 0.0598 AC: 309 AN: 5170

South Asian (SAS) AF: 0.307 AC: 1479 AN: 4812

European-Finnish (FIN) AF: 0.131 AC: 1389 AN: 10576

Middle Eastern (MID) AF: 0.253 AC: 74 AN: 292

European-Non Finnish (NFE) AF: 0.170 AC: 11572 AN: 67970

Other (OTH) AF: 0.212 AC: 447 AN: 2106

Alfa AF: 0.182 Hom.: 2600

Bravo AF: 0.198

Asia WGS AF: 0.180 AC: 627 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	1.0
DANN	Benign	0.29
PhyloP100		-0.22
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: rs16931011; hg19: chr12-26728515; COSMIC: COSV101190371;