NM_002224.4:c.2268C>T

Variant names:

• chr6-33670403-C-T
• rs2229634
• NM_002224.4:c.2268C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_002224.4(ITPR3):​c.2268C>T​(p.Gly756Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,613,780 control chromosomes in the GnomAD database, including 86,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6340 hom., cov: 32)
  • Exomes 𝑓: 0.32 (79707 hom.)
• Consequence: ITPR3 NM_002224.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -3.15
• Publications: 47 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 6-33670403-C-T is Benign according to our data. Variant chr6-33670403-C-T is described in ClinVar as Benign. ClinVar VariationId is 1293559.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR3	NM_002224.4	c.2268C>T	p.Gly756Gly	synonymous_variant	Exon 19 of 58	ENST00000605930.3	NP_002215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3	c.2268C>T	p.Gly756Gly	synonymous_variant	Exon 19 of 58	1	NM_002224.4	ENSP00000475177.1
ITPR3	ENST00000374316.9	c.2268C>T	p.Gly756Gly	synonymous_variant	Exon 20 of 59	5		ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.276 AC: 42000 AN: 151924 Hom.: 6331 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.478

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.267

GnomAD2 exomes AF: 0.327 AC: 82161 AN: 251298 AF XY: 0.340

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.263

Gnomad ASJ exome AF: 0.185

Gnomad EAS exome AF: 0.477

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.323 AC: 471951 AN: 1461738 Hom.: 79707 Cov.: 64 AF XY: 0.329 AC XY: 238983 AN XY: 727176

African (AFR) AF: 0.176 AC: 5905 AN: 33480

American (AMR) AF: 0.259 AC: 11571 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4897 AN: 26134

East Asian (EAS) AF: 0.465 AC: 18450 AN: 39698

South Asian (SAS) AF: 0.506 AC: 43672 AN: 86258

European-Finnish (FIN) AF: 0.364 AC: 19418 AN: 53310

Middle Eastern (MID) AF: 0.277 AC: 1600 AN: 5768

European-Non Finnish (NFE) AF: 0.312 AC: 347131 AN: 1111972

Other (OTH) AF: 0.320 AC: 19307 AN: 60394

GnomAD4 genome AF: 0.276 AC: 42030 AN: 152042 Hom.: 6340 Cov.: 32 AF XY: 0.283 AC XY: 21055 AN XY: 74304

African (AFR) AF: 0.178 AC: 7369 AN: 41472

American (AMR) AF: 0.258 AC: 3946 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 640 AN: 3472

East Asian (EAS) AF: 0.478 AC: 2461 AN: 5150

South Asian (SAS) AF: 0.512 AC: 2467 AN: 4818

European-Finnish (FIN) AF: 0.362 AC: 3820 AN: 10566

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20364 AN: 67960

Other (OTH) AF: 0.272 AC: 576 AN: 2114

Alfa AF: 0.294 Hom.: 32635

Bravo AF: 0.260

Asia WGS AF: 0.510 AC: 1770 AN: 3478

EpiCase AF: 0.296

EpiControl AF: 0.298

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

ITPR3-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.5
DANN	Benign	0.82
PhyloP100		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2229634; hg19: chr6-33638180; COSMIC: COSV65409465;