12-26434645-G-A

Variant names:

• chr12-26434645-G-A
• rs10771283
• NM_002223.4:c.6769+1576C>T

Variant summary

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

The NM_002223.4(ITPR2):​c.6769+1576C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.733 in 152,008 control chromosomes in the GnomAD database, including 41,294 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 0.73 (41294 hom., cov: 31)
• Consequence: ITPR2 NM_002223.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.864
• 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=-1.04).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.797 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.6769+1576C>T		intron	N/A	NP_002214.2
	ITPR2	NM_001414174.1		c.6766+1576C>T		intron	N/A	NP_001401103.1
	ITPR2	NM_001414175.1		c.6550+1576C>T		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.6769+1576C>T		intron	N/A	ENSP00000370744.3
	ITPR2	ENST00000451599.6	TSL:1	n.*1288+1576C>T		intron	N/A	ENSP00000408287.2

Frequencies

GnomAD3 genomes AF: 0.733 AC: 111359 AN: 151888 Hom.: 41266 Cov.: 31

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.889

Gnomad AMR AF: 0.630

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.691

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.803

Gnomad OTH AF: 0.721

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

GnomAD4 genome AF: 0.733 AC: 111436 AN: 152008 Hom.: 41294 Cov.: 31 AF XY: 0.729 AC XY: 54122 AN XY: 74290

African (AFR) AF: 0.667 AC: 27638 AN: 41456

American (AMR) AF: 0.630 AC: 9616 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 2373 AN: 3470

East Asian (EAS) AF: 0.590 AC: 3043 AN: 5154

South Asian (SAS) AF: 0.692 AC: 3324 AN: 4802

European-Finnish (FIN) AF: 0.788 AC: 8343 AN: 10582

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.803 AC: 54567 AN: 67962

Other (OTH) AF: 0.722 AC: 1524 AN: 2110

Alfa AF: 0.775 Hom.: 24045

Bravo AF: 0.717

Asia WGS AF: 0.643 AC: 2239 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.2
DANN	Benign	0.67
PhyloP100		0.86
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: rs10771283; hg19: chr12-26587578;