6-33669130-C-T

Variant names:

• chr6-33669130-C-T
• rs2077163
• NM_002224.4:c.2163C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_002224.4(ITPR3):​c.2163C>T​(p.His721His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 1,613,712 control chromosomes in the GnomAD database, including 230,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.48 (18178 hom., cov: 33)
  • Exomes 𝑓: 0.54 (212079 hom.)
• Consequence: ITPR3 NM_002224.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -3.04
• Publications: 23 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 6-33669130-C-T is Benign according to our data. Variant chr6-33669130-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060407.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-3.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.579 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.2163C>T	p.His721His	synonymous	Exon 18 of 58	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.2163C>T	p.His721His	synonymous	Exon 18 of 58	ENSP00000475177.1	Q14573
	ITPR3	ENST00000374316.9	TSL:5	c.2163C>T	p.His721His	synonymous	Exon 19 of 59	ENSP00000363435.4	Q14573
	ITPR3	ENST00000931640.1		c.2163C>T	p.His721His	synonymous	Exon 18 of 58	ENSP00000601699.1

Frequencies

GnomAD3 genomes AF: 0.484 AC: 73581 AN: 152002 Hom.: 18161 Cov.: 33

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.494

GnomAD2 exomes AF: 0.515 AC: 129267 AN: 250930 AF XY: 0.524

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.451

Gnomad ASJ exome AF: 0.463

Gnomad EAS exome AF: 0.525

Gnomad FIN exome AF: 0.487

Gnomad NFE exome AF: 0.537

Gnomad OTH exome AF: 0.519

GnomAD4 exome AF: 0.537 AC: 784285 AN: 1461592 Hom.: 212079 Cov.: 54 AF XY: 0.539 AC XY: 391927 AN XY: 727106

African (AFR) AF: 0.381 AC: 12758 AN: 33474

American (AMR) AF: 0.452 AC: 20187 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 11914 AN: 26120

East Asian (EAS) AF: 0.540 AC: 21450 AN: 39694

South Asian (SAS) AF: 0.605 AC: 52164 AN: 86232

European-Finnish (FIN) AF: 0.493 AC: 26317 AN: 53344

Middle Eastern (MID) AF: 0.511 AC: 2933 AN: 5740

European-Non Finnish (NFE) AF: 0.544 AC: 604628 AN: 1111898

Other (OTH) AF: 0.529 AC: 31934 AN: 60386

GnomAD4 genome AF: 0.484 AC: 73632 AN: 152120 Hom.: 18178 Cov.: 33 AF XY: 0.483 AC XY: 35905 AN XY: 74376

African (AFR) AF: 0.388 AC: 16098 AN: 41484

American (AMR) AF: 0.475 AC: 7261 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 1534 AN: 3468

East Asian (EAS) AF: 0.531 AC: 2747 AN: 5172

South Asian (SAS) AF: 0.597 AC: 2880 AN: 4824

European-Finnish (FIN) AF: 0.488 AC: 5174 AN: 10594

Middle Eastern (MID) AF: 0.510 AC: 149 AN: 292

European-Non Finnish (NFE) AF: 0.534 AC: 36276 AN: 67968

Other (OTH) AF: 0.497 AC: 1050 AN: 2112

Alfa AF: 0.509 Hom.: 56526

Bravo AF: 0.477

Asia WGS AF: 0.588 AC: 2043 AN: 3478

EpiCase AF: 0.530

EpiControl AF: 0.540

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ITPR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	2.0
DANN	Benign	0.87
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=79/21	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: rs2077163; hg19: chr6-33636907; COSMIC: COSV65409798;