NM_002223.4:c.7375C>G

Variant names:

• chr12-26411344-G-C
• NM_002223.4:c.7375C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002223.4(ITPR2):​c.7375C>G​(p.Pro2459Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR2 NM_002223.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00500
• Publications: 0 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):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08336604).

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.7375C>G	p.Pro2459Ala	missense	Exon 52 of 57	NP_002214.2	Q14571-1
	ITPR2	NM_001414174.1		c.7372C>G	p.Pro2458Ala	missense	Exon 52 of 57	NP_001401103.1
	ITPR2	NM_001414175.1		c.7156C>G	p.Pro2386Ala	missense	Exon 50 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.7375C>G	p.Pro2459Ala	missense	Exon 52 of 57	ENSP00000370744.3	Q14571-1
	ITPR2	ENST00000451599.6	TSL:1	n.*1894C>G		non_coding_transcript_exon	Exon 15 of 18	ENSP00000408287.2	H7C2X9
	ITPR2	ENST00000451599.6	TSL:1	n.*1894C>G		3_prime_UTR	Exon 15 of 18	ENSP00000408287.2	H7C2X9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.80
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-1.4	N
PhyloP100		-0.0050
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.95	N
REVEL	Benign	0.27
Sift	Benign	0.90	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.35		Loss of methylation at K2454 (P = 0.0653)
MVP		0.45
MPC		0.77
ClinPred		0.033	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.018
gMVP		0.28
Mutation Taster		=80/20	polymorphism

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

hg19: chr12-26564277;