rs1553666546

Variant names:

• chr3-4645609-G-A
• rs1553666546
• NM_001378452.1:c.736G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-4645609-G-A
• chr3-4645609-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001378452.1(ITPR1):​c.736G>A​(p.Glu246Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 9.89

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ITPR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 5.5951 (above the threshold of 3.09). Trascript score misZ: 6.2026 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 3-4645609-G-A is Pathogenic according to our data. Variant chr3-4645609-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 453136.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.736G>A	p.Glu246Lys	missense_variant	Exon 10 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.736G>A	p.Glu246Lys	missense_variant	Exon 10 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.736G>A	p.Glu246Lys	missense_variant	Exon 10 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.736G>A	p.Glu246Lys	missense_variant	Exon 10 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.736G>A	p.Glu246Lys	missense_variant	Exon 10 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.736G>A	p.Glu246Lys	missense_variant	Exon 10 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.736G>A	p.Glu246Lys	missense_variant	Exon 10 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.736G>A	p.Glu246Lys	missense_variant	Exon 10 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.736G>A	p.Glu246Lys	missense_variant	Exon 10 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.736G>A	p.Glu246Lys	missense_variant	Exon 8 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.736G>A	p.Glu246Lys	missense_variant	Exon 10 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.736G>A	p.Glu246Lys	missense_variant	Exon 10 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Gillespie syndrome;C1847725:Spinocerebellar ataxia type 15/16;C1861732:Spinocerebellar ataxia type 29 Pathogenic:1

Jun 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Feb 26, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 29 Pathogenic:1

Feb 09, 2018

Schule lab, Hertie Institute for Clinical Brain Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Uncertain:1

Oct 31, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The E246K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E246K variant is not observed in large population cohorts (Lek et al., 2016). The E246K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	.;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;M;.;.;M;.;.;.;M;M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	D;D;.;D;D;.;N;.;.;.;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;.;D;D;.;D;.;.;.;D
Sift4G	Uncertain	0.0020	D;D;.;.;D;.;D;.;.;.;D
Polyphen		0.96, 1.0	.;.;.;.;.;.;D;.;D;.;.
Vest4		0.92
MutPred		0.72		Loss of ubiquitination at K249 (P = 0.0256);Loss of ubiquitination at K249 (P = 0.0256);Loss of ubiquitination at K249 (P = 0.0256);Loss of ubiquitination at K249 (P = 0.0256);Loss of ubiquitination at K249 (P = 0.0256);Loss of ubiquitination at K249 (P = 0.0256);Loss of ubiquitination at K249 (P = 0.0256);Loss of ubiquitination at K249 (P = 0.0256);Loss of ubiquitination at K249 (P = 0.0256);Loss of ubiquitination at K249 (P = 0.0256);Loss of ubiquitination at K249 (P = 0.0256);
MVP		0.97
MPC		1.9
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.80
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553666546; hg19: chr3-4687293; COSMIC: COSV56983139;