12-26338542-T-C

Variant names:

• chr12-26338542-T-C
• rs1049376
• NM_002223.4:c.*855A>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.*855A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 152,422 control chromosomes in the GnomAD database, including 6,252 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 0.27 (6233 hom., cov: 32)
  • Exomes 𝑓: 0.35 (19 hom.)
• Consequence: ITPR2 NM_002223.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0380
• Publications: 15 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

ENSG00000255968 (HGNC:58268):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.502 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.*855A>G		3_prime_UTR	Exon 57 of 57	NP_002214.2
	ITPR2	NM_001414174.1		c.*855A>G		3_prime_UTR	Exon 57 of 57	NP_001401103.1
	ITPR2	NM_001414175.1		c.*855A>G		3_prime_UTR	Exon 55 of 55	NP_001401104.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR2	ENST00000381340.8	TSL:1 MANE Select	c.*855A>G		3_prime_UTR	Exon 57 of 57	ENSP00000370744.3
	ENSG00000255968	ENST00000535324.1	TSL:3	n.52+19538T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41239 AN: 152014 Hom.: 6226 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.352 AC: 102 AN: 290 Hom.: 19 Cov.: 0 AF XY: 0.351 AC XY: 61 AN XY: 174

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.349 AC: 99 AN: 284

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.271 AC: 41259 AN: 152132 Hom.: 6233 Cov.: 32 AF XY: 0.275 AC XY: 20460 AN XY: 74360

African (AFR) AF: 0.190 AC: 7905 AN: 41514

American (AMR) AF: 0.402 AC: 6142 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 716 AN: 3472

East Asian (EAS) AF: 0.518 AC: 2677 AN: 5168

South Asian (SAS) AF: 0.173 AC: 836 AN: 4830

European-Finnish (FIN) AF: 0.349 AC: 3683 AN: 10562

Middle Eastern (MID) AF: 0.192 AC: 56 AN: 292

European-Non Finnish (NFE) AF: 0.274 AC: 18604 AN: 67986

Other (OTH) AF: 0.250 AC: 529 AN: 2114

Alfa AF: 0.277 Hom.: 5932

Bravo AF: 0.273

Asia WGS AF: 0.297 AC: 1035 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.0
DANN	Benign	0.63
PhyloP100		0.038
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: rs1049376; hg19: chr12-26491475;