Genetic Variant ITPR1:p.Arg269Arg (chr3-4645678-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4BP7

The NM_001378452.1(ITPR1):c.805C>A(p.Arg269Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R269R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ITPR1
NM_001378452.1 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.13

Publications

22 publications found

Variant links:

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: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
spinocerebellar ataxia type 29
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
spinocerebellar ataxia type 15/16
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ITPR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.17).

BP7

Synonymous conserved (PhyloP=2.13 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ITPR1	NM_001378452.1 link	c.805C>A	p.Arg269Arg	synonymous_variant	Exon 10 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 link	c.805C>A	p.Arg269Arg	synonymous_variant	Exon 10 of 61		NP_001161744.1
ITPR1	NM_001099952.4 link	c.805C>A	p.Arg269Arg	synonymous_variant	Exon 10 of 59		NP_001093422.2
ITPR1	NM_002222.7 link	c.805C>A	p.Arg269Arg	synonymous_variant	Exon 10 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ITPR1	ENST00000649015.2 link	c.805C>A	p.Arg269Arg	synonymous_variant	Exon 10 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12 link	c.805C>A	p.Arg269Arg	synonymous_variant	Exon 10 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1 link	c.805C>A	p.Arg269Arg	synonymous_variant	Exon 10 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1 link	c.805C>A	p.Arg269Arg	synonymous_variant	Exon 10 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5 link	c.805C>A	p.Arg269Arg	synonymous_variant	Exon 10 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1 link	c.805C>A	p.Arg269Arg	synonymous_variant	Exon 8 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10 link	c.805C>A	p.Arg269Arg	synonymous_variant	Exon 10 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8 link	c.805C>A	p.Arg269Arg	synonymous_variant	Exon 10 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461282

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726878

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111744

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

2.1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over