rs2291862

Variant names:

• chr3-4800547-C-T
• rs2291862
• NM_001378452.1:c.7054C>T
• ITPR1 p.Leu2352Leu

Your query was ambiguous. Multiple possible variants found:

• chr3-4800547-C-T
• chr3-4800547-C-G

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:12
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, ClinGen, Orphanet
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• 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 ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378452.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.7054C>T	p.Leu2352Leu	synonymous	Exon 54 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.7009C>T	p.Leu2337Leu	synonymous	Exon 53 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.6910C>T	p.Leu2304Leu	synonymous	Exon 51 of 59	NP_001093422.2	Q14643-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.7054C>T	p.Leu2352Leu	synonymous	Exon 54 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.7030C>T	p.Leu2344Leu	synonymous	Exon 54 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.7027C>T	p.Leu2343Leu	synonymous	Exon 54 of 62	ENSP00000498014.1	A0A3B3IU04

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	Gillespie syndrome (1)
-	-	1	Spinocerebellar ataxia type 15/16 (1)
-	-	1	Spinocerebellar ataxia type 29 (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2291862;

hg19: chr3-4842231;

COSMIC: COSV56973948;