rs2306875

Variant names:

• chr3-4670729-G-A
• rs2306875
• NM_001378452.1:c.2007G>A
• ITPR1 p.Lys669Lys

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:11
• 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: 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)

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 VariationId 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.

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.2007G>A	p.Lys669Lys	splice_region synonymous	Exon 20 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.1962G>A	p.Lys654Lys	splice_region synonymous	Exon 19 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.2007G>A	p.Lys669Lys	splice_region synonymous	Exon 20 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.2007G>A	p.Lys669Lys	splice_region synonymous	Exon 20 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.2007G>A	p.Lys669Lys	splice_region synonymous	Exon 20 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.2007G>A	p.Lys669Lys	splice_region synonymous	Exon 20 of 62	ENSP00000498014.1	A0A3B3IU04

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	2	Spinocerebellar ataxia type 29 (2)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	Gillespie syndrome (1)
-	-	1	Spinocerebellar ataxia type 15/16 (1)

Computational scores

Source: dbNSFP v4.9

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

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

Other links and lift over

dbSNP: rs2306875;

hg19: chr3-4712413;

COSMIC: COSV56976735;