rs2306877

Positions:

• chr3-4675127-A-C
• chr3-4675127-A-G
• chr3-4675127-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378452.1(ITPR1):​c.2658A>C​(p.Leu886Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,605,562 control chromosomes in the GnomAD database, including 43,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5980 hom., cov: 32)
  • Exomes 𝑓: 0.21 (37154 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.52

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-4675127-A-C is Benign according to our data. Variant chr3-4675127-A-C is described in ClinVar as [Benign]. Clinvar id is 129299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4675127-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2658A>C	p.Leu886Leu	synonymous_variant	23/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2613A>C	p.Leu871Leu	synonymous_variant	22/61		NP_001161744.1
ITPR1	NM_001099952.4	c.2658A>C	p.Leu886Leu	synonymous_variant	23/59		NP_001093422.2
ITPR1	NM_002222.7	c.2613A>C	p.Leu871Leu	synonymous_variant	22/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2658A>C	p.Leu886Leu	synonymous_variant	23/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2658A>C	p.Leu886Leu	synonymous_variant	23/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2658A>C	p.Leu886Leu	synonymous_variant	23/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.2613A>C	p.Leu871Leu	synonymous_variant	22/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.2613A>C	p.Leu871Leu	synonymous_variant	22/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2613A>C	p.Leu871Leu	synonymous_variant	20/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2658A>C	p.Leu886Leu	synonymous_variant	23/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2613A>C	p.Leu871Leu	synonymous_variant	22/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.495A>C	p.Leu165Leu	synonymous_variant	4/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.-16A>C		upstream_gene_variant				ENSP00000498149.1

Frequencies

GnomAD3 genomes AF: 0.270 AC: 40967 AN: 151992 Hom.: 5968 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.244

GnomAD3 exomes AF: 0.271 AC: 67189 AN: 247978 Hom.: 10383 AF XY: 0.266 AC XY: 35786 AN XY: 134610

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.417

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.289

Gnomad SAS exome AF: 0.374

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.214 AC: 310432 AN: 1453452 Hom.: 37154 Cov.: 29 AF XY: 0.217 AC XY: 157259 AN XY: 723564

Gnomad4 AFR exome AF: 0.374

Gnomad4 AMR exome AF: 0.402

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.290

Gnomad4 SAS exome AF: 0.376

Gnomad4 FIN exome AF: 0.294

Gnomad4 NFE exome AF: 0.183

Gnomad4 OTH exome AF: 0.217

GnomAD4 genome AF: 0.270 AC: 41031 AN: 152110 Hom.: 5980 Cov.: 32 AF XY: 0.276 AC XY: 20548 AN XY: 74344

Gnomad4 AFR AF: 0.366

Gnomad4 AMR AF: 0.330

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.290

Gnomad4 SAS AF: 0.402

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.242

Alfa AF: 0.207 Hom.: 5976

Bravo AF: 0.272

Asia WGS AF: 0.359 AC: 1245 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Spinocerebellar ataxia type 29 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Autosomal dominant cerebellar ataxia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.1
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 13

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

Publications

LitVar

Other links and lift over

dbSNP: rs2306877; hg19: chr3-4716811; COSMIC: COSV56983696; COSMIC: COSV56983696;