rs34491089

Variant names:

• chr3-4788027-A-G
• rs34491089
• NM_001378452.1:c.6696A>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.6696A>G​(p.Lys2232Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,612,788 control chromosomes in the GnomAD database, including 715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (59 hom., cov: 31)
  • Exomes 𝑓: 0.026 (656 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.576
• Publications: 5 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, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.59).
• BP6: Variant 3-4788027-A-G is Benign according to our data. Variant chr3-4788027-A-G is described in ClinVar as Benign. ClinVar VariationId is 129300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.576 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0573 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.6696A>G	p.Lys2232Lys	synonymous	Exon 52 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.6651A>G	p.Lys2217Lys	synonymous	Exon 51 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.6552A>G	p.Lys2184Lys	synonymous	Exon 49 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.6696A>G	p.Lys2232Lys	synonymous	Exon 52 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.6672A>G	p.Lys2224Lys	synonymous	Exon 52 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.6669A>G	p.Lys2223Lys	synonymous	Exon 52 of 62	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3262 AN: 152222 Hom.: 59 Cov.: 31

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0475

Gnomad FIN AF: 0.0409

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.0302 AC: 7474 AN: 247118 AF XY: 0.0302

Gnomad AFR exome AF: 0.00445

Gnomad AMR exome AF: 0.0631

Gnomad ASJ exome AF: 0.0270

Gnomad EAS exome AF: 0.000335

Gnomad FIN exome AF: 0.0410

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0326

GnomAD4 exome AF: 0.0265 AC: 38686 AN: 1460448 Hom.: 656 Cov.: 30 AF XY: 0.0269 AC XY: 19528 AN XY: 726386

African (AFR) AF: 0.00379 AC: 127 AN: 33470

American (AMR) AF: 0.0591 AC: 2637 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.0258 AC: 675 AN: 26114

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39698

South Asian (SAS) AF: 0.0454 AC: 3900 AN: 85874

European-Finnish (FIN) AF: 0.0417 AC: 2224 AN: 53370

Middle Eastern (MID) AF: 0.0179 AC: 103 AN: 5766

European-Non Finnish (NFE) AF: 0.0248 AC: 27507 AN: 1111218

Other (OTH) AF: 0.0250 AC: 1507 AN: 60344

GnomAD4 genome AF: 0.0214 AC: 3262 AN: 152340 Hom.: 59 Cov.: 31 AF XY: 0.0225 AC XY: 1673 AN XY: 74492

African (AFR) AF: 0.00418 AC: 174 AN: 41588

American (AMR) AF: 0.0354 AC: 542 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0469 AC: 226 AN: 4818

European-Finnish (FIN) AF: 0.0409 AC: 434 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0254 AC: 1731 AN: 68032

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.0227 Hom.: 23

Bravo AF: 0.0198

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	ITPR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.5
DANN	Benign	0.43
PhyloP100		0.58
Mutation Taster		=99/1	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: rs34491089; hg19: chr3-4829711;