12-26336611-G-T

Variant names:

• chr12-26336611-G-T
• rs1049380
• NM_002223.4:c.*2786C>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.*2786C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 152,022 control chromosomes in the GnomAD database, including 37,050 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 0.69 (37050 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: ITPR2 NM_002223.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.305
• Publications: 34 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)

ITPR2-AS2 (HGNC:58268):

ENSG00000256185 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.804 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.*2786C>A		3_prime_UTR	Exon 57 of 57	NP_002214.2	Q14571-1
	ITPR2	NM_001414174.1		c.*2786C>A		3_prime_UTR	Exon 57 of 57	NP_001401103.1
	ITPR2	NM_001414175.1		c.*2786C>A		3_prime_UTR	Exon 55 of 55	NP_001401104.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR2	ENST00000381340.8	TSL:1 MANE Select	c.*2786C>A		3_prime_UTR	Exon 57 of 57	ENSP00000370744.3	Q14571-1
	ITPR2-AS2	ENST00000535324.1	TSL:3	n.52+17607G>T		intron	N/A
	ENSG00000256185	ENST00000537724.1	TSL:3	n.126+214C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.694 AC: 105440 AN: 151904 Hom.: 37001 Cov.: 32

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.824

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.728

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

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) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.694 AC: 105543 AN: 152022 Hom.: 37050 Cov.: 32 AF XY: 0.691 AC XY: 51362 AN XY: 74336

African (AFR) AF: 0.688 AC: 28533 AN: 41446

American (AMR) AF: 0.586 AC: 8943 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 2755 AN: 3470

East Asian (EAS) AF: 0.483 AC: 2498 AN: 5174

South Asian (SAS) AF: 0.825 AC: 3981 AN: 4824

European-Finnish (FIN) AF: 0.652 AC: 6880 AN: 10558

Middle Eastern (MID) AF: 0.806 AC: 237 AN: 294

European-Non Finnish (NFE) AF: 0.726 AC: 49374 AN: 67982

Other (OTH) AF: 0.730 AC: 1541 AN: 2110

Alfa AF: 0.720 Hom.: 66319

Bravo AF: 0.688

Asia WGS AF: 0.697 AC: 2402 AN: 3450

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.57
PhyloP100		0.30

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: rs1049380; hg19: chr12-26489544;