dbSNP rs2002610: ITPR2:c.6343-15487G>A (chr12-26459137-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002223.4(ITPR2):c.6343-15487G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0239 in 152,222 control chromosomes in the GnomAD database, including 133 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 0.024 ( 133 hom., cov: 32)

Consequence

ITPR2
NM_002223.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.283

Publications

2 publications found

Variant links:

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

ITPR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR2	NM_002223.4 link	c.6343-15487G>A		intron_variant	Intron 45 of 56	ENST00000381340.8	NP_002214.2	Q14571-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR2	ENST00000381340.8 link	c.6343-15487G>A		intron_variant	Intron 45 of 56	1	NM_002223.4	ENSP00000370744.3		Q14571-1
ITPR2	ENST00000451599.6 link	n.*862-15487G>A		intron_variant	Intron 8 of 17	1		ENSP00000408287.2		H7C2X9

Frequencies

GnomAD3 genomes

AF:

0.0239

AC:

3630

AN:

152104

Hom.:

129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0138

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.191

Gnomad SAS

AF:

0.0618

Gnomad FIN

AF:

0.0324

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0126

Gnomad OTH

AF:

0.0206

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0239

AC:

3639

AN:

152222

Hom.:

133

Cov.:

AF XY:

0.0265

AC XY:

1969

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0196

AC:

815

AN:

41536

American (AMR)

AF:

0.0138

AC:

211

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

AN:

3468

East Asian (EAS)

AF:

0.191

AC:

991

AN:

5178

South Asian (SAS)

AF:

0.0615

AC:

296

AN:

4816

European-Finnish (FIN)

AF:

0.0324

AC:

344

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0126

AC:

855

AN:

68008

Other (OTH)

AF:

0.0251

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

171

343

514

686

857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0156

Hom.:

Bravo

AF:

0.0216

Asia WGS

AF:

0.117

AC:

406

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

0.28

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over