rs2296339

Variant names:

• chr6-33662847-C-T
• rs2296339
• NM_002224.4:c.859-64C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002224.4(ITPR3):​c.859-64C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,526,604 control chromosomes in the GnomAD database, including 192,166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.50 (19470 hom., cov: 31)
  • Exomes 𝑓: 0.50 (172696 hom.)
• Consequence: ITPR3 NM_002224.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0440
• Publications: 8 publications found

Genes affected

ITPR3 (HGNC:6182): (inositol 1,4,5-trisphosphate receptor type 3) This gene encodes a receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium. The receptor contains a calcium channel at the C-terminus and the ligand-binding site at the N-terminus. Knockout studies in mice suggest that type 2 and type 3 inositol 1,4,5-trisphosphate receptors play a key role in exocrine secretion underlying energy metabolism and growth. [provided by RefSeq, Aug 2010]

ITPR3 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease, demyelinating, type 1J

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-33662847-C-T is Benign according to our data. Variant chr6-33662847-C-T is described in ClinVar as Benign. ClinVar VariationId is 1293546.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR3	NM_002224.4	c.859-64C>T		intron_variant	Intron 8 of 57	ENST00000605930.3	NP_002215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3	c.859-64C>T		intron_variant	Intron 8 of 57	1	NM_002224.4	ENSP00000475177.1
ITPR3	ENST00000374316.9	c.859-64C>T		intron_variant	Intron 9 of 58	5		ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76243 AN: 151818 Hom.: 19463 Cov.: 31

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.658

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.502

GnomAD4 exome AF: 0.497 AC: 683506 AN: 1374666 Hom.: 172696 Cov.: 25 AF XY: 0.495 AC XY: 335831 AN XY: 678766

African (AFR) AF: 0.524 AC: 16430 AN: 31334

American (AMR) AF: 0.512 AC: 18175 AN: 35530

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 15971 AN: 24388

East Asian (EAS) AF: 0.252 AC: 9042 AN: 35850

South Asian (SAS) AF: 0.388 AC: 30245 AN: 77868

European-Finnish (FIN) AF: 0.470 AC: 22777 AN: 48504

Middle Eastern (MID) AF: 0.526 AC: 2895 AN: 5508

European-Non Finnish (NFE) AF: 0.510 AC: 540101 AN: 1058516

Other (OTH) AF: 0.488 AC: 27870 AN: 57168

GnomAD4 genome AF: 0.502 AC: 76288 AN: 151938 Hom.: 19470 Cov.: 31 AF XY: 0.498 AC XY: 36980 AN XY: 74256

African (AFR) AF: 0.514 AC: 21296 AN: 41432

American (AMR) AF: 0.517 AC: 7908 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 2279 AN: 3464

East Asian (EAS) AF: 0.214 AC: 1103 AN: 5148

South Asian (SAS) AF: 0.376 AC: 1809 AN: 4808

European-Finnish (FIN) AF: 0.480 AC: 5066 AN: 10554

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35220 AN: 67930

Other (OTH) AF: 0.496 AC: 1047 AN: 2110

Alfa AF: 0.512 Hom.: 28924

Bravo AF: 0.505

Asia WGS AF: 0.296 AC: 1034 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.1
DANN	Benign	0.77
PhyloP100		0.044
Mutation Taster		=100/0	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: rs2296339; hg19: chr6-33630624; COSMIC: COSV65412839;