rs2281919

Positions:

• chr6-33695394-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002224.4(ITPR3):​c.7947+309A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 556,010 control chromosomes in the GnomAD database, including 8,430 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (2055 hom., cov: 33)
  • Exomes 𝑓: 0.17 (6375 hom.)
• Consequence: ITPR3 NM_002224.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.173

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]

UQCC2 (HGNC:21237): (ubiquinol-cytochrome c reductase complex assembly factor 2) This gene encodes a nucleoid protein localized to the mitochondria inner membrane. The encoded protein affects regulation of insulin secretion, mitochondrial ATP production, and myogenesis through modulation of mitochondrial respiratory chain activity. [provided by RefSeq, Oct 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR3	NM_002224.4	c.7947+309A>C		intron_variant		ENST00000605930.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR3	ENST00000605930.3	c.7947+309A>C		intron_variant		1	NM_002224.4	P1
UQCC2	ENST00000374231.8	c.*85T>G		3_prime_UTR_variant	5/5	3
ITPR3	ENST00000374316.9	c.7947+309A>C		intron_variant		5		P1
UQCC2	ENST00000606961.1	n.3264T>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22872 AN: 152126 Hom.: 2054 Cov.: 33

Gnomad AFR AF: 0.0843

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.0458

Gnomad SAS AF: 0.0704

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.181

GnomAD3 exomes AF: 0.146 AC: 7043 AN: 48332 Hom.: 652 AF XY: 0.142 AC XY: 3506 AN XY: 24668

Gnomad AFR exome AF: 0.0817

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.240

Gnomad EAS exome AF: 0.0407

Gnomad SAS exome AF: 0.0762

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.169 AC: 68173 AN: 403766 Hom.: 6375 Cov.: 2 AF XY: 0.165 AC XY: 34754 AN XY: 210674

Gnomad4 AFR exome AF: 0.0826

Gnomad4 AMR exome AF: 0.161

Gnomad4 ASJ exome AF: 0.227

Gnomad4 EAS exome AF: 0.0892

Gnomad4 SAS exome AF: 0.0771

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.198

Gnomad4 OTH exome AF: 0.170

GnomAD4 genome AF: 0.150 AC: 22891 AN: 152244 Hom.: 2055 Cov.: 33 AF XY: 0.144 AC XY: 10728 AN XY: 74444

Gnomad4 AFR AF: 0.0844

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.0457

Gnomad4 SAS AF: 0.0707

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.198

Gnomad4 OTH AF: 0.178

Alfa AF: 0.178 Hom.: 621

Bravo AF: 0.153

Asia WGS AF: 0.0690 AC: 240 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.82

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: rs2281919; hg19: chr6-33663171;