chr12-26427978-T-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_002223.4(ITPR2):c.6880A>G(p.Ile2294Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ITPR2
NM_002223.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.336

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.061783165).

BP6

Variant 12-26427978-T-C is Benign according to our data. Variant chr12-26427978-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3530904.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR2	NM_002223.4 link	c.6880A>G	p.Ile2294Val	missense_variant	Exon 49 of 57	ENST00000381340.8	NP_002214.2	Q14571-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPR2	ENST00000381340.8 link	c.6880A>G	p.Ile2294Val	missense_variant	Exon 49 of 57	1	NM_002223.4	ENSP00000370744.3	Q14571-1
ITPR2	ENST00000451599.6 link	n.*1399A>G		non_coding_transcript_exon_variant	Exon 12 of 18	1		ENSP00000408287.2	H7C2X9
ITPR2	ENST00000451599.6 link	n.*1399A>G		3_prime_UTR_variant	Exon 12 of 18	1		ENSP00000408287.2	H7C2X9
ITPR2	ENST00000538984.1 link	n.-41A>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248304

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461022

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726822

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 03, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.21

DANN

Benign

0.82

DEOGEN2

Uncertain

0.52

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.74

M_CAP

Benign

0.066

MetaRNN

Benign

0.062

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.34

PrimateAI

Benign

0.29

PROVEAN

Benign

0.27

REVEL

Benign

0.17

Sift

Benign

0.93

Sift4G

Benign

0.68

Polyphen

0.0

Vest4

0.11

MutPred

0.34

Gain of catalytic residue at I2299 (P = 0.0011);

MVP

0.33

MPC

0.19

ClinPred

0.020

GERP RS

-4.6

Varity_R

0.022

gMVP

0.27

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over