rs868822649

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001378452.1(ITPR1):c.7528G>A(p.Gly2510Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,468 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2510A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ITPR1
NM_001378452.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.05

Publications

0 publications found

Variant links:

Genes affected

ITPR1 (HGNC:6180): (inositol 1,4,5-trisphosphate receptor type 1) This gene encodes an intracellular receptor for inositol 1,4,5-trisphosphate. Upon stimulation by inositol 1,4,5-trisphosphate, this receptor mediates calcium release from the endoplasmic reticulum. Mutations in this gene cause spinocerebellar ataxia type 15, a disease associated with an heterogeneous group of cerebellar disorders. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

ITPR1 Gene-Disease associations (from GenCC):

aniridia-cerebellar ataxia-intellectual disability syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
spinocerebellar ataxia type 29
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
spinocerebellar ataxia type 15/16
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ITPR1 links:

ENSG00000235978 (HGNC:):

ENSG00000235978 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.21322584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1 link	c.7528G>A	p.Gly2510Arg	missense_variant	Exon 57 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 link	c.7483G>A	p.Gly2495Arg	missense_variant	Exon 56 of 61		NP_001161744.1	Q14643-2
ITPR1	NM_001099952.4 link	c.7384G>A	p.Gly2462Arg	missense_variant	Exon 54 of 59		NP_001093422.2	Q14643-3B4DER3Q59H91
ITPR1	NM_002222.7 link	c.7339G>A	p.Gly2447Arg	missense_variant	Exon 53 of 58		NP_002213.5	Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPR1	ENST00000649015.2 link	c.7528G>A	p.Gly2510Arg	missense_variant	Exon 57 of 62		NM_001378452.1	ENSP00000497605.1	Q14643-1
ITPR1	ENST00000354582.12 link	c.7504G>A	p.Gly2502Arg	missense_variant	Exon 57 of 62	5		ENSP00000346595.8	A0A3F2YNW8
ITPR1	ENST00000648266.1 link	c.7501G>A	p.Gly2501Arg	missense_variant	Exon 57 of 62			ENSP00000498014.1	A0A3B3IU04
ITPR1	ENST00000650294.1 link	c.7486G>A	p.Gly2496Arg	missense_variant	Exon 56 of 61			ENSP00000498056.1	A0A3B3ITU8
ITPR1	ENST00000443694.5 link	c.7483G>A	p.Gly2495Arg	missense_variant	Exon 56 of 61	1		ENSP00000401671.2	Q14643-2
ITPR1	ENST00000648309.1 link	c.7456G>A	p.Gly2486Arg	missense_variant	Exon 54 of 59			ENSP00000497026.1	Q14643-5
ITPR1	ENST00000357086.10 link	c.7384G>A	p.Gly2462Arg	missense_variant	Exon 54 of 59	1		ENSP00000349597.4	Q14643-3
ITPR1	ENST00000456211.8 link	c.7339G>A	p.Gly2447Arg	missense_variant	Exon 53 of 58	1		ENSP00000397885.2	Q14643-4
ITPR1	ENST00000648038.1 link	c.5290G>A	p.Gly1764Arg	missense_variant	Exon 37 of 42			ENSP00000497872.1	A0A3B3ITQ1
ITPR1	ENST00000648431.1 link	c.4705G>A	p.Gly1569Arg	missense_variant	Exon 34 of 39			ENSP00000498149.1	A0A3B3IU05
ITPR1	ENST00000648212.1 link	c.4468G>A	p.Gly1490Arg	missense_variant	Exon 34 of 39			ENSP00000498022.1	A0A3B3IU13

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248946

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461306

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726918

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1111564

Other (OTH)

AF:

0.0000331

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5208

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2016

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.7339G>A (p.G2447R) alteration is located in exon 53 (coding exon 51) of the ITPR1 gene. This alteration results from a G to A substitution at nucleotide position 7339, causing the glycine (G) at amino acid position 2447 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jun 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ITPR1 protein function. ClinVar contains an entry for this variant (Variation ID: 447599). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2447 of the ITPR1 protein (p.Gly2447Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

.;.;.;.;.;.;.;D;.;.;.

Eigen

Benign

-0.095

Eigen_PC

Benign

0.037

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D;D;D;.;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.21

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

1.3

.;.;.;.;.;.;.;L;.;.;.

PhyloP100

5.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.0

N;N;.;N;.;N;.;.;.;N;.

REVEL

Uncertain

0.39

Sift

Benign

0.047

D;T;.;D;.;D;.;.;.;T;.

Sift4G

Benign

0.10

T;T;.;T;.;T;.;.;.;T;.

Polyphen

0.42, 0.0010

.;.;.;.;.;B;.;B;.;.;.

Vest4

0.27

MutPred

0.31

.;.;.;.;.;.;.;Loss of glycosylation at S2509 (P = 0.0357);.;.;.;

MVP

0.74

MPC

1.0

ClinPred

0.43

GERP RS

5.0

Varity_R

0.085

gMVP

0.77

Mutation Taster

=73/27

polymorphism

(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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rs868822649

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over