NM_001378452.1:c.2007G>A

Variant names:

• chr3-4670729-G-A
• rs2306875
• NM_001378452.1:c.2007G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001378452.1(ITPR1):​c.2007G>A​(p.Lys669Lys) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.668 in 1,569,864 control chromosomes in the GnomAD database, including 354,237 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34961 hom., cov: 32)
  • Exomes 𝑓: 0.67 (319276 hom.)
• Consequence: ITPR1 NM_001378452.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.5656
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.61
• Publications: 26 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)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 3-4670729-G-A is Benign according to our data. Variant chr3-4670729-G-A is described in ClinVar as [Benign]. Clinvar id is 129298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2007G>A	p.Lys669Lys	splice_region_variant, synonymous_variant	Exon 20 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.1962G>A	p.Lys654Lys	splice_region_variant, synonymous_variant	Exon 19 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.2007G>A	p.Lys669Lys	splice_region_variant, synonymous_variant	Exon 20 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.1962G>A	p.Lys654Lys	splice_region_variant, synonymous_variant	Exon 19 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2007G>A	p.Lys669Lys	splice_region_variant, synonymous_variant	Exon 20 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2007G>A	p.Lys669Lys	splice_region_variant, synonymous_variant	Exon 20 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2007G>A	p.Lys669Lys	splice_region_variant, synonymous_variant	Exon 20 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.1962G>A	p.Lys654Lys	splice_region_variant, synonymous_variant	Exon 19 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.1962G>A	p.Lys654Lys	splice_region_variant, synonymous_variant	Exon 19 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.1962G>A	p.Lys654Lys	splice_region_variant, synonymous_variant	Exon 17 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2007G>A	p.Lys669Lys	splice_region_variant, synonymous_variant	Exon 20 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.1962G>A	p.Lys654Lys	splice_region_variant, synonymous_variant	Exon 19 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.-157G>A		upstream_gene_variant				ENSP00000497872.1

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102489 AN: 151924 Hom.: 34924 Cov.: 32

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.646

GnomAD2 exomes AF: 0.648 AC: 129425 AN: 199708 AF XY: 0.643

Gnomad AFR exome AF: 0.684

Gnomad AMR exome AF: 0.716

Gnomad ASJ exome AF: 0.600

Gnomad EAS exome AF: 0.354

Gnomad FIN exome AF: 0.696

Gnomad NFE exome AF: 0.669

Gnomad OTH exome AF: 0.647

GnomAD4 exome AF: 0.668 AC: 946701 AN: 1417822 Hom.: 319276 Cov.: 29 AF XY: 0.666 AC XY: 468217 AN XY: 702542

African (AFR) AF: 0.688 AC: 22441 AN: 32602

American (AMR) AF: 0.711 AC: 27596 AN: 38830

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 15315 AN: 25492

East Asian (EAS) AF: 0.348 AC: 13389 AN: 38522

South Asian (SAS) AF: 0.640 AC: 52162 AN: 81442

European-Finnish (FIN) AF: 0.698 AC: 36006 AN: 51620

Middle Eastern (MID) AF: 0.609 AC: 3438 AN: 5646

European-Non Finnish (NFE) AF: 0.680 AC: 737973 AN: 1084686

Other (OTH) AF: 0.651 AC: 38381 AN: 58982

GnomAD4 genome AF: 0.675 AC: 102584 AN: 152042 Hom.: 34961 Cov.: 32 AF XY: 0.673 AC XY: 49998 AN XY: 74330

African (AFR) AF: 0.697 AC: 28883 AN: 41450

American (AMR) AF: 0.701 AC: 10720 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2114 AN: 3466

East Asian (EAS) AF: 0.354 AC: 1832 AN: 5170

South Asian (SAS) AF: 0.637 AC: 3066 AN: 4814

European-Finnish (FIN) AF: 0.692 AC: 7325 AN: 10580

Middle Eastern (MID) AF: 0.616 AC: 180 AN: 292

European-Non Finnish (NFE) AF: 0.684 AC: 46468 AN: 67964

Other (OTH) AF: 0.644 AC: 1356 AN: 2104

Alfa AF: 0.670 Hom.: 99226

Bravo AF: 0.671

Asia WGS AF: 0.536 AC: 1864 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2019

Athena Diagnostics

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 29 Benign:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

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. -

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 12, 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 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	-0.29
CADD	Benign	21
DANN	Benign	0.89
PhyloP100		4.6
Mutation Taster		=30/70	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.57
dbscSNV1_RF	Benign	0.48
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: 29

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2306875; hg19: chr3-4712413; COSMIC: COSV56976735;