6-33691695-C-G

Position:

• chr6-33691695-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_002224.4(ITPR3):​c.7306C>G​(p.Leu2436Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 1,613,126 control chromosomes in the GnomAD database, including 209,135 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.47 (18127 hom., cov: 30)
  • Exomes 𝑓: 0.50 (191008 hom.)
• Consequence: ITPR3 NM_002224.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.687

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ITPR3. . Gene score misZ 4.5522 (greater than the threshold 3.09). Trascript score misZ 5.2589 (greater than threshold 3.09). GenCC has associacion of gene with Charcot-Marie-Tooth disease, demyelinating, type 1J.
• BP4: Computational evidence support a benign effect (MetaRNN=8.319047E-7).
• BP6: Variant 6-33691695-C-G is Benign according to our data. Variant chr6-33691695-C-G is described in ClinVar as [Benign]. Clinvar id is 1251401.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR3	NM_002224.4	c.7306C>G	p.Leu2436Val	missense_variant	53/58	ENST00000605930.3	NP_002215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3	c.7306C>G	p.Leu2436Val	missense_variant	53/58	1	NM_002224.4	ENSP00000475177.1
ITPR3	ENST00000374316.9	c.7306C>G	p.Leu2436Val	missense_variant	54/59	5		ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70811 AN: 151716 Hom.: 18107 Cov.: 30

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.901

Gnomad SAS AF: 0.806

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.447

GnomAD3 exomes AF: 0.572 AC: 143588 AN: 251116 Hom.: 44492 AF XY: 0.582 AC XY: 79059 AN XY: 135726

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.655

Gnomad ASJ exome AF: 0.471

Gnomad EAS exome AF: 0.918

Gnomad SAS exome AF: 0.780

Gnomad FIN exome AF: 0.615

Gnomad NFE exome AF: 0.478

Gnomad OTH exome AF: 0.525

GnomAD4 exome AF: 0.498 AC: 727342 AN: 1461292 Hom.: 191008 Cov.: 49 AF XY: 0.508 AC XY: 369063 AN XY: 726976

Gnomad4 AFR exome AF: 0.290

Gnomad4 AMR exome AF: 0.640

Gnomad4 ASJ exome AF: 0.476

Gnomad4 EAS exome AF: 0.865

Gnomad4 SAS exome AF: 0.781

Gnomad4 FIN exome AF: 0.609

Gnomad4 NFE exome AF: 0.458

Gnomad4 OTH exome AF: 0.501

GnomAD4 genome AF: 0.467 AC: 70861 AN: 151834 Hom.: 18127 Cov.: 30 AF XY: 0.486 AC XY: 36039 AN XY: 74160

Gnomad4 AFR AF: 0.299

Gnomad4 AMR AF: 0.550

Gnomad4 ASJ AF: 0.484

Gnomad4 EAS AF: 0.901

Gnomad4 SAS AF: 0.807

Gnomad4 FIN AF: 0.625

Gnomad4 NFE AF: 0.468

Gnomad4 OTH AF: 0.453

Alfa AF: 0.471 Hom.: 5581

Bravo AF: 0.449

TwinsUK AF: 0.447 AC: 1656

ALSPAC AF: 0.463 AC: 1785

ESP6500AA AF: 0.308 AC: 1356

ESP6500EA AF: 0.460 AC: 3956

ExAC AF: 0.567 AC: 68894

Asia WGS AF: 0.786 AC: 2732 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

ITPR3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	1.7
DANN	Benign	0.21
DEOGEN2	Uncertain	0.51	D;D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.041	.;T
MetaRNN	Benign	8.3e-7	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.0	N;.
REVEL	Benign	0.076
Sift	Benign	0.76	T;.
Sift4G	Benign	0.69	T;T
Polyphen		0.0	B;B
Vest4		0.043
MPC		0.70
ClinPred		0.0059	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229642; hg19: chr6-33659472; COSMIC: COSV65291190; COSMIC: COSV65291190;