rs41290672

Variant names:

• chr3-4800591-C-T
• rs41290672
• NM_001378452.1:c.7098C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-4800591-C-T
• chr3-4800591-C-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001378452.1(ITPR1):​c.7098C>T​(p.Gly2366Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000614 in 1,613,926 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (1 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.37
• Publications: 2 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 3-4800591-C-T is Benign according to our data. Variant chr3-4800591-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 345759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000374 (57/152338) while in subpopulation SAS AF = 0.00104 (5/4828). AF 95% confidence interval is 0.000408. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.7098C>T	p.Gly2366Gly	synonymous	Exon 54 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.7053C>T	p.Gly2351Gly	synonymous	Exon 53 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.6954C>T	p.Gly2318Gly	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.7098C>T	p.Gly2366Gly	synonymous	Exon 54 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.7074C>T	p.Gly2358Gly	synonymous	Exon 54 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.7071C>T	p.Gly2357Gly	synonymous	Exon 54 of 62	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000393 AC: 98 AN: 249156 AF XY: 0.000422

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000487

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000639 AC: 934 AN: 1461588 Hom.: 1 Cov.: 32 AF XY: 0.000627 AC XY: 456 AN XY: 727090

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000788 AC: 68 AN: 86246

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000721 AC: 802 AN: 1111772

Other (OTH) AF: 0.000563 AC: 34 AN: 60370

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74486

African (AFR) AF: 0.000192 AC: 8 AN: 41574

American (AMR) AF: 0.000588 AC: 9 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000360 Hom.: 0

Bravo AF: 0.000321

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.2
DANN	Benign	0.72
PhyloP100		-1.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41290672; hg19: chr3-4842275; COSMIC: COSV100233925;