12-26792480-C-T

Variant names:

• chr12-26792480-C-T
• rs2122268
• NM_002223.4:c.93-2253G>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.93-2253G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 151,832 control chromosomes in the GnomAD database, including 67,780 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 0.94 (67780 hom., cov: 27)
• Consequence: ITPR2 NM_002223.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0750
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 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.93-2253G>A		intron	N/A	NP_002214.2
	ITPR2	NM_001414174.1		c.93-2253G>A		intron	N/A	NP_001401103.1
	ITPR2	NM_001414175.1		c.93-2253G>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.93-2253G>A		intron	N/A	ENSP00000370744.3
	ITPR2	ENST00000242737.5	TSL:1	c.93-2253G>A		intron	N/A	ENSP00000242737.5
	ITPR2	ENST00000545235.1	TSL:1	n.92+40210G>A		intron	N/A	ENSP00000440548.1

Frequencies

GnomAD3 genomes AF: 0.944 AC: 143216 AN: 151714 Hom.: 67723 Cov.: 27

Gnomad AFR AF: 0.984

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.974

Gnomad ASJ AF: 0.933

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.958

Gnomad FIN AF: 0.869

Gnomad MID AF: 0.924

Gnomad NFE AF: 0.920

Gnomad OTH AF: 0.946

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

GnomAD4 genome AF: 0.944 AC: 143332 AN: 151832 Hom.: 67780 Cov.: 27 AF XY: 0.942 AC XY: 69932 AN XY: 74202

African (AFR) AF: 0.984 AC: 40785 AN: 41450

American (AMR) AF: 0.974 AC: 14868 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.933 AC: 3236 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5120 AN: 5122

South Asian (SAS) AF: 0.957 AC: 4562 AN: 4766

European-Finnish (FIN) AF: 0.869 AC: 9167 AN: 10544

Middle Eastern (MID) AF: 0.925 AC: 272 AN: 294

European-Non Finnish (NFE) AF: 0.920 AC: 62436 AN: 67896

Other (OTH) AF: 0.947 AC: 1996 AN: 2108

Alfa AF: 0.935 Hom.: 125083

Bravo AF: 0.953

Asia WGS AF: 0.978 AC: 3400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.7
DANN	Benign	0.17
PhyloP100		0.075
Mutation Taster		=98/2	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: rs2122268; hg19: chr12-26945413;