chr12-26340222-G-A

Variant names:

• chr12-26340222-G-A
• rs200691111
• NM_002223.4:c.7964C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002223.4(ITPR2):​c.7964C>T​(p.Ser2655Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,610,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ITPR2 NM_002223.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51
• 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)

ITPR2-AS2 (HGNC:58268):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053634644).

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.7964C>T	p.Ser2655Leu	missense	Exon 56 of 57	NP_002214.2	Q14571-1
	ITPR2	NM_001414174.1		c.7961C>T	p.Ser2654Leu	missense	Exon 56 of 57	NP_001401103.1
	ITPR2	NM_001414175.1		c.7745C>T	p.Ser2582Leu	missense	Exon 54 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.7964C>T	p.Ser2655Leu	missense	Exon 56 of 57	ENSP00000370744.3	Q14571-1
	ITPR2-AS2	ENST00000535324.1	TSL:3	n.52+21218G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000285 AC: 70 AN: 245880 AF XY: 0.000337

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.000285

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000139 AC: 203 AN: 1458012 Hom.: 0 Cov.: 31 AF XY: 0.000145 AC XY: 105 AN XY: 725108

African (AFR) AF: 0.0000599 AC: 2 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44176

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.00 AC: 0 AN: 85072

European-Finnish (FIN) AF: 0.00157 AC: 84 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000919 AC: 102 AN: 1110390

Other (OTH) AF: 0.000232 AC: 14 AN: 60274

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74426

African (AFR) AF: 0.0000722 AC: 3 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000273 AC: 33

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	0.082
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.0023
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.090
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.020	D
Polyphen		0.35	B
Vest4		0.40
MutPred		0.31		Loss of phosphorylation at S2655 (P = 0.0497)
MVP		0.49
MPC		0.74
ClinPred		0.11	T
GERP RS		5.6
Varity_R		0.25
gMVP		0.25
Mutation Taster		=82/18	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

dbSNP: rs200691111; hg19: chr12-26493155; COSMIC: COSV104430481; COSMIC: COSV104430481;