rs2274198

Variant names:

• chr6-33670880-G-A
• rs2274198
• NM_002224.4:c.2586+65G>A

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.2586+65G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,572,694 control chromosomes in the GnomAD database, including 96,521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.33 (8277 hom., cov: 32)
  • Exomes 𝑓: 0.35 (88244 hom.)
• Consequence: ITPR3 NM_002224.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.859
• Publications: 5 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=-0.85).
• BP6: Variant 6-33670880-G-A is Benign according to our data. Variant chr6-33670880-G-A is described in ClinVar as Benign. ClinVar VariationId is 1177808.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 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.2586+65G>A		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.2586+65G>A		intron	N/A	ENSP00000475177.1
	ITPR3	ENST00000374316.9	TSL:5	c.2586+65G>A		intron	N/A	ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49867 AN: 151844 Hom.: 8256 Cov.: 32

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.311

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.315

GnomAD4 exome AF: 0.349 AC: 495597 AN: 1420732 Hom.: 88244 AF XY: 0.349 AC XY: 246226 AN XY: 704872

African (AFR) AF: 0.311 AC: 10153 AN: 32648

American (AMR) AF: 0.328 AC: 13968 AN: 42538

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 5283 AN: 24398

East Asian (EAS) AF: 0.495 AC: 19515 AN: 39412

South Asian (SAS) AF: 0.404 AC: 33251 AN: 82362

European-Finnish (FIN) AF: 0.324 AC: 14121 AN: 43646

Middle Eastern (MID) AF: 0.269 AC: 1488 AN: 5524

European-Non Finnish (NFE) AF: 0.346 AC: 377788 AN: 1091216

Other (OTH) AF: 0.340 AC: 20030 AN: 58988

GnomAD4 genome AF: 0.329 AC: 49941 AN: 151962 Hom.: 8277 Cov.: 32 AF XY: 0.330 AC XY: 24500 AN XY: 74282

African (AFR) AF: 0.320 AC: 13252 AN: 41436

American (AMR) AF: 0.312 AC: 4767 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 755 AN: 3466

East Asian (EAS) AF: 0.473 AC: 2427 AN: 5134

South Asian (SAS) AF: 0.409 AC: 1970 AN: 4822

European-Finnish (FIN) AF: 0.312 AC: 3300 AN: 10576

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22378 AN: 67936

Other (OTH) AF: 0.316 AC: 667 AN: 2110

Alfa AF: 0.317 Hom.: 1006

Bravo AF: 0.328

Asia WGS AF: 0.434 AC: 1509 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	-0.85
CADD	Benign	0.13
DANN	Benign	0.62
PhyloP100		-0.86
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: rs2274198; hg19: chr6-33638657; COSMIC: COSV107480007;