rs2274200

Variant names:

• chr6-33657919-T-C
• rs2274200
• NM_002224.4:c.283-13T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002224.4(ITPR3):​c.283-13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,611,136 control chromosomes in the GnomAD database, including 45,897 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.20 (3762 hom., cov: 31)
  • Exomes 𝑓: 0.23 (42135 hom.)
• Consequence: ITPR3 NM_002224.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.194
• Publications: 14 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 -10 ACMG points.

• BP6: Variant 6-33657919-T-C is Benign according to our data. Variant chr6-33657919-T-C is described in ClinVar as Benign. ClinVar VariationId is 1251103.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.282 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR3	NM_002224.4	MANE Select	c.283-13T>C		intron	N/A	NP_002215.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR3	ENST00000605930.3	TSL:1 MANE Select	c.283-13T>C		intron	N/A	ENSP00000475177.1
	ITPR3	ENST00000374316.9	TSL:5	c.283-13T>C		intron	N/A	ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30764 AN: 151790 Hom.: 3765 Cov.: 31

Gnomad AFR AF: 0.0641

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.257 AC: 64141 AN: 249106 AF XY: 0.260

Gnomad AFR exome AF: 0.0580

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.267

Gnomad EAS exome AF: 0.291

Gnomad FIN exome AF: 0.343

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.235 AC: 342860 AN: 1459228 Hom.: 42135 Cov.: 32 AF XY: 0.238 AC XY: 172447 AN XY: 725908

African (AFR) AF: 0.0552 AC: 1847 AN: 33448

American (AMR) AF: 0.319 AC: 14208 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 6980 AN: 26100

East Asian (EAS) AF: 0.263 AC: 10430 AN: 39622

South Asian (SAS) AF: 0.284 AC: 24435 AN: 86078

European-Finnish (FIN) AF: 0.336 AC: 17855 AN: 53176

Middle Eastern (MID) AF: 0.207 AC: 1191 AN: 5760

European-Non Finnish (NFE) AF: 0.227 AC: 252412 AN: 1110290

Other (OTH) AF: 0.224 AC: 13502 AN: 60282

GnomAD4 genome AF: 0.203 AC: 30762 AN: 151908 Hom.: 3762 Cov.: 31 AF XY: 0.211 AC XY: 15639 AN XY: 74230

African (AFR) AF: 0.0639 AC: 2650 AN: 41452

American (AMR) AF: 0.254 AC: 3880 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 983 AN: 3462

East Asian (EAS) AF: 0.281 AC: 1449 AN: 5164

South Asian (SAS) AF: 0.295 AC: 1418 AN: 4808

European-Finnish (FIN) AF: 0.351 AC: 3694 AN: 10536

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16043 AN: 67910

Other (OTH) AF: 0.173 AC: 366 AN: 2112

Alfa AF: 0.211 Hom.: 5413

Bravo AF: 0.188

Asia WGS AF: 0.220 AC: 767 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.68
CADD	Benign	17
DANN	Benign	0.77
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: -33

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2274200; hg19: chr6-33625696; COSMIC: COSV65407076;