12-26719797-T-C

Variant names:

• chr12-26719797-T-C
• rs12823128
• NM_002223.4:c.525+2600A>G

Variant summary

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

The NM_002223.4(ITPR2):​c.525+2600A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 152,020 control chromosomes in the GnomAD database, including 10,383 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 0.33 (10383 hom., cov: 31)
• Consequence: ITPR2 NM_002223.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.546
• Publications: 11 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR2	NM_002223.4	c.525+2600A>G		intron_variant	Intron 5 of 56	ENST00000381340.8	NP_002214.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR2	ENST00000381340.8	c.525+2600A>G		intron_variant	Intron 5 of 56	1	NM_002223.4	ENSP00000370744.3
ITPR2	ENST00000545235.1	n.*214+2600A>G		intron_variant	Intron 4 of 4	1		ENSP00000440548.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49438 AN: 151902 Hom.: 10392 Cov.: 31

Gnomad AFR AF: 0.0829

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.481

Gnomad OTH AF: 0.340

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

GnomAD4 genome AF: 0.325 AC: 49410 AN: 152020 Hom.: 10383 Cov.: 31 AF XY: 0.318 AC XY: 23617 AN XY: 74300

African (AFR) AF: 0.0826 AC: 3430 AN: 41524

American (AMR) AF: 0.290 AC: 4415 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1186 AN: 3470

East Asian (EAS) AF: 0.184 AC: 952 AN: 5168

South Asian (SAS) AF: 0.213 AC: 1027 AN: 4820

European-Finnish (FIN) AF: 0.423 AC: 4457 AN: 10540

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.481 AC: 32665 AN: 67940

Other (OTH) AF: 0.335 AC: 708 AN: 2112

Alfa AF: 0.393 Hom.: 2263

Bravo AF: 0.308

Asia WGS AF: 0.182 AC: 633 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.9
DANN	Benign	0.49
PhyloP100		0.55
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: rs12823128; hg19: chr12-26872730;