3-4800547-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378452.1(ITPR1):c.7054C>G(p.Leu2352Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L2352L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ITPR1
NM_001378452.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0270

Publications

24 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1 link	c.7054C>G	p.Leu2352Val	missense_variant	Exon 54 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 link	c.7009C>G	p.Leu2337Val	missense_variant	Exon 53 of 61		NP_001161744.1	Q14643-2
ITPR1	NM_001099952.4 link	c.6910C>G	p.Leu2304Val	missense_variant	Exon 51 of 59		NP_001093422.2	Q14643-3B4DER3Q59H91
ITPR1	NM_002222.7 link	c.6865C>G	p.Leu2289Val	missense_variant	Exon 50 of 58		NP_002213.5	Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPR1	ENST00000649015.2 link	c.7054C>G	p.Leu2352Val	missense_variant	Exon 54 of 62		NM_001378452.1	ENSP00000497605.1	Q14643-1
ITPR1	ENST00000354582.12 link	c.7030C>G	p.Leu2344Val	missense_variant	Exon 54 of 62	5		ENSP00000346595.8	A0A3F2YNW8
ITPR1	ENST00000648266.1 link	c.7027C>G	p.Leu2343Val	missense_variant	Exon 54 of 62			ENSP00000498014.1	A0A3B3IU04
ITPR1	ENST00000650294.1 link	c.7012C>G	p.Leu2338Val	missense_variant	Exon 53 of 61			ENSP00000498056.1	A0A3B3ITU8
ITPR1	ENST00000443694.5 link	c.7009C>G	p.Leu2337Val	missense_variant	Exon 53 of 61	1		ENSP00000401671.2	Q14643-2
ITPR1	ENST00000648309.1 link	c.6982C>G	p.Leu2328Val	missense_variant	Exon 51 of 59			ENSP00000497026.1	Q14643-5
ITPR1	ENST00000357086.10 link	c.6910C>G	p.Leu2304Val	missense_variant	Exon 51 of 59	1		ENSP00000349597.4	Q14643-3
ITPR1	ENST00000456211.8 link	c.6865C>G	p.Leu2289Val	missense_variant	Exon 50 of 58	1		ENSP00000397885.2	Q14643-4
ITPR1	ENST00000648038.1 link	c.4816C>G	p.Leu1606Val	missense_variant	Exon 34 of 42			ENSP00000497872.1	A0A3B3ITQ1
ITPR1	ENST00000648431.1 link	c.4231C>G	p.Leu1411Val	missense_variant	Exon 31 of 39			ENSP00000498149.1	A0A3B3IU05
ITPR1	ENST00000648212.1 link	c.3994C>G	p.Leu1332Val	missense_variant	Exon 31 of 39			ENSP00000498022.1	A0A3B3IU13

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461680

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111846

Other (OTH)

AF:

0.00

AC:

AN:

60372

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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

12830

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Benign

4.8

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.56

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

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.70

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.3

.;.;.;.;.;.;M;.;.;.

PhyloP100

0.027

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.9

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

REVEL

Uncertain

0.49

Sift

Benign

0.040

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

Sift4G

Benign

0.062

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

Polyphen

0.97

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

Vest4

0.74

MutPred

0.32

.;.;.;.;.;.;Loss of stability (P = 0.1117);.;.;.;

MVP

0.66

MPC

2.0

ClinPred

0.81

GERP RS

-0.92

Varity_R

0.11

gMVP

0.69

Mutation Taster

=71/29

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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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