NM_002224.4:c.2007-91C>G

Variant names:

• chr6-33668883-C-G
• rs2296336
• NM_002224.4:c.2007-91C>G

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.2007-91C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,371,970 control chromosomes in the GnomAD database, including 73,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6398 hom., cov: 32)
  • Exomes 𝑓: 0.32 (66933 hom.)
• Consequence: ITPR3 NM_002224.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.93
• Publications: 15 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-33668883-C-G is Benign according to our data. Variant chr6-33668883-C-G is described in ClinVar as Benign. ClinVar VariationId is 1247153.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002224.4. 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
	ITPR3	NM_002224.4	MANE Select	c.2007-91C>G		intron	N/A	NP_002215.2	Q14573

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR3	ENST00000605930.3	TSL:1 MANE Select	c.2007-91C>G		intron	N/A	ENSP00000475177.1	Q14573
	ITPR3	ENST00000374316.9	TSL:5	c.2007-91C>G		intron	N/A	ENSP00000363435.4	Q14573
	ITPR3	ENST00000931640.1		c.2007-91C>G		intron	N/A	ENSP00000601699.1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42209 AN: 151986 Hom.: 6390 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.268

GnomAD4 exome AF: 0.323 AC: 393561 AN: 1219866 Hom.: 66933 AF XY: 0.328 AC XY: 199692 AN XY: 608010

African (AFR) AF: 0.176 AC: 5031 AN: 28624

American (AMR) AF: 0.260 AC: 8957 AN: 34486

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 3898 AN: 21002

East Asian (EAS) AF: 0.477 AC: 17779 AN: 37238

South Asian (SAS) AF: 0.506 AC: 35889 AN: 70950

European-Finnish (FIN) AF: 0.363 AC: 15052 AN: 41448

Middle Eastern (MID) AF: 0.278 AC: 1363 AN: 4902

European-Non Finnish (NFE) AF: 0.311 AC: 288993 AN: 929196

Other (OTH) AF: 0.319 AC: 16599 AN: 52020

GnomAD4 genome AF: 0.278 AC: 42238 AN: 152104 Hom.: 6398 Cov.: 32 AF XY: 0.285 AC XY: 21150 AN XY: 74336

African (AFR) AF: 0.178 AC: 7404 AN: 41512

American (AMR) AF: 0.258 AC: 3951 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3468

East Asian (EAS) AF: 0.487 AC: 2504 AN: 5144

South Asian (SAS) AF: 0.512 AC: 2467 AN: 4822

European-Finnish (FIN) AF: 0.361 AC: 3823 AN: 10576

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

European-Non Finnish (NFE) AF: 0.301 AC: 20485 AN: 67970

Other (OTH) AF: 0.273 AC: 577 AN: 2112

Alfa AF: 0.277 Hom.: 807

Bravo AF: 0.262

Asia WGS AF: 0.514 AC: 1785 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.43
PhyloP100		-1.9
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: rs2296336; hg19: chr6-33636660; COSMIC: COSV65406610;