NM_001378452.1:c.7054C>T

Variant names:

• chr3-4800547-C-T
• rs2291862
• NM_001378452.1:c.7054C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378452.1(ITPR1):​c.7054C>T​(p.Leu2352Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,613,528 control chromosomes in the GnomAD database, including 66,485 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5109 hom., cov: 32)
  • Exomes 𝑓: 0.29 (61376 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0270
• Publications: 24 publications found

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)

ENSG00000235978 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-4800547-C-T is Benign according to our data. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in CliVar as Benign. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.027 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7054C>T	p.Leu2352Leu	synonymous_variant	Exon 54 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.7009C>T	p.Leu2337Leu	synonymous_variant	Exon 53 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.6910C>T	p.Leu2304Leu	synonymous_variant	Exon 51 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.6865C>T	p.Leu2289Leu	synonymous_variant	Exon 50 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7054C>T	p.Leu2352Leu	synonymous_variant	Exon 54 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7030C>T	p.Leu2344Leu	synonymous_variant	Exon 54 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7027C>T	p.Leu2343Leu	synonymous_variant	Exon 54 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7012C>T	p.Leu2338Leu	synonymous_variant	Exon 53 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7009C>T	p.Leu2337Leu	synonymous_variant	Exon 53 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.6982C>T	p.Leu2328Leu	synonymous_variant	Exon 51 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.6910C>T	p.Leu2304Leu	synonymous_variant	Exon 51 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.6865C>T	p.Leu2289Leu	synonymous_variant	Exon 50 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.4816C>T	p.Leu1606Leu	synonymous_variant	Exon 34 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4231C>T	p.Leu1411Leu	synonymous_variant	Exon 31 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.3994C>T	p.Leu1332Leu	synonymous_variant	Exon 31 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37797 AN: 152088 Hom.: 5099 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.273

GnomAD2 exomes AF: 0.293 AC: 73061 AN: 249164 AF XY: 0.292

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.370

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.413

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.283

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.286 AC: 418458 AN: 1461322 Hom.: 61376 Cov.: 35 AF XY: 0.286 AC XY: 208252 AN XY: 726968

African (AFR) AF: 0.127 AC: 4253 AN: 33472

American (AMR) AF: 0.364 AC: 16279 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 8464 AN: 26134

East Asian (EAS) AF: 0.405 AC: 16088 AN: 39692

South Asian (SAS) AF: 0.296 AC: 25496 AN: 86224

European-Finnish (FIN) AF: 0.229 AC: 12249 AN: 53400

Middle Eastern (MID) AF: 0.346 AC: 1993 AN: 5766

European-Non Finnish (NFE) AF: 0.285 AC: 316597 AN: 1111568

Other (OTH) AF: 0.282 AC: 17039 AN: 60358

GnomAD4 genome AF: 0.249 AC: 37856 AN: 152206 Hom.: 5109 Cov.: 32 AF XY: 0.249 AC XY: 18493 AN XY: 74402

African (AFR) AF: 0.141 AC: 5853 AN: 41542

American (AMR) AF: 0.316 AC: 4837 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1129 AN: 3472

East Asian (EAS) AF: 0.389 AC: 2012 AN: 5176

South Asian (SAS) AF: 0.282 AC: 1363 AN: 4828

European-Finnish (FIN) AF: 0.238 AC: 2522 AN: 10590

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19204 AN: 67988

Other (OTH) AF: 0.278 AC: 587 AN: 2114

Alfa AF: 0.272 Hom.: 12830

Bravo AF: 0.252

Asia WGS AF: 0.306 AC: 1068 AN: 3478

EpiCase AF: 0.294

EpiControl AF: 0.293

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 04, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Jul 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Gillespie syndrome Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant cerebellar ataxia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Spinocerebellar ataxia type 29 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 15/16 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.45
DANN	Benign	0.57
PhyloP100		0.027
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2291862; hg19: chr3-4842231; COSMIC: COSV56973948;