chr12-26645456-G-T

Variant names:

• chr12-26645456-G-T
• rs4964010
• NM_002223.4:c.2740+8520C>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.2740+8520C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.651 in 152,028 control chromosomes in the GnomAD database, including 32,561 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 0.65 (32561 hom., cov: 32)
• Consequence: ITPR2 NM_002223.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.205
• Publications: 2 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

ENSG00000234428 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.873 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.2740+8520C>A		intron	N/A	NP_002214.2
	ITPR2	NM_001414174.1		c.2737+8520C>A		intron	N/A	NP_001401103.1
	ITPR2	NM_001414175.1		c.2740+8520C>A		intron	N/A	NP_001401104.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR2	ENST00000381340.8	TSL:1 MANE Select	c.2740+8520C>A		intron	N/A	ENSP00000370744.3
	ENSG00000234428	ENST00000414098.2	TSL:5	n.150-3297G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98869 AN: 151910 Hom.: 32534 Cov.: 32

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.733

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.894

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.652

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

GnomAD4 genome AF: 0.651 AC: 98945 AN: 152028 Hom.: 32561 Cov.: 32 AF XY: 0.653 AC XY: 48506 AN XY: 74314

African (AFR) AF: 0.604 AC: 25032 AN: 41448

American (AMR) AF: 0.734 AC: 11219 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2349 AN: 3470

East Asian (EAS) AF: 0.894 AC: 4630 AN: 5178

South Asian (SAS) AF: 0.621 AC: 2987 AN: 4812

European-Finnish (FIN) AF: 0.660 AC: 6974 AN: 10564

Middle Eastern (MID) AF: 0.623 AC: 182 AN: 292

European-Non Finnish (NFE) AF: 0.643 AC: 43684 AN: 67950

Other (OTH) AF: 0.651 AC: 1377 AN: 2116

Alfa AF: 0.654 Hom.: 5201

Bravo AF: 0.659

Asia WGS AF: 0.759 AC: 2638 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.74
DANN	Benign	0.35
PhyloP100		-0.20
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: rs4964010; hg19: chr12-26798389;