12-26411391-A-G

Variant names:

• chr12-26411391-A-G
• rs369918783
• NM_002223.4:c.7328T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002223.4(ITPR2):​c.7328T>C​(p.Met2443Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,613,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2443R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: ITPR2 NM_002223.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36
• Publications: 4 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012725025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR2	NM_002223.4	c.7328T>C	p.Met2443Thr	missense_variant	Exon 52 of 57	ENST00000381340.8	NP_002214.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR2	ENST00000381340.8	c.7328T>C	p.Met2443Thr	missense_variant	Exon 52 of 57	1	NM_002223.4	ENSP00000370744.3

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000265 AC: 66 AN: 248852 AF XY: 0.000200

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00351

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1460740 Hom.: 0 Cov.: 29 AF XY: 0.0000894 AC XY: 65 AN XY: 726708

African (AFR) AF: 0.0000897 AC: 3 AN: 33448

American (AMR) AF: 0.0000448 AC: 2 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00298 AC: 118 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111208

Other (OTH) AF: 0.000149 AC: 9 AN: 60320

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74492

African (AFR) AF: 0.000192 AC: 8 AN: 41580

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000967 Hom.: 0

Bravo AF: 0.000242

ExAC AF: 0.000199 AC: 24

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.85
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.12	N
PhyloP100		2.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.22
Sift	Benign	0.77	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.24
MVP		0.70
MPC		0.91
ClinPred		0.024	T
GERP RS		4.1
Varity_R		0.055
gMVP		0.49
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs369918783; hg19: chr12-26564324; COSMIC: COSV67264217;