12-26538618-C-T

Variant names:

• chr12-26538618-C-T
• rs9669395
• NM_002223.4:c.5073+11629G>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.5073+11629G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 151,334 control chromosomes in the GnomAD database, including 28,137 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 0.57 (28137 hom., cov: 30)
• Consequence: ITPR2 NM_002223.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.281
• 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: Orphanet, Labcorp Genetics (formerly Invitae)

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 (NFE) allele frequency at 95% confidence interval = 0.757 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR2	NM_002223.4	MANE Select	c.5073+11629G>A		intron	N/A	NP_002214.2	Q14571-1
	ITPR2	NM_001414174.1		c.5070+11629G>A		intron	N/A	NP_001401103.1
	ITPR2	NM_001414175.1		c.5073+11629G>A		intron	N/A	NP_001401104.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR2	ENST00000381340.8	TSL:1 MANE Select	c.5073+11629G>A		intron	N/A	ENSP00000370744.3	Q14571-1

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85663 AN: 151218 Hom.: 28136 Cov.: 30

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.672

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.738

Gnomad MID AF: 0.526

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.585

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

GnomAD4 genome AF: 0.566 AC: 85678 AN: 151334 Hom.: 28137 Cov.: 30 AF XY: 0.562 AC XY: 41552 AN XY: 73928

African (AFR) AF: 0.257 AC: 10601 AN: 41176

American (AMR) AF: 0.476 AC: 7237 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2244 AN: 3466

East Asian (EAS) AF: 0.255 AC: 1310 AN: 5130

South Asian (SAS) AF: 0.602 AC: 2888 AN: 4796

European-Finnish (FIN) AF: 0.738 AC: 7708 AN: 10450

Middle Eastern (MID) AF: 0.531 AC: 153 AN: 288

European-Non Finnish (NFE) AF: 0.762 AC: 51711 AN: 67826

Other (OTH) AF: 0.580 AC: 1217 AN: 2098

Alfa AF: 0.641 Hom.: 4197

Bravo AF: 0.530

Asia WGS AF: 0.425 AC: 1478 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.5
DANN	Benign	0.61
PhyloP100		0.28
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: rs9669395; hg19: chr12-26691551;