rs2281919

Variant names:

• chr6-33695394-A-C
• rs2281919
• NM_002224.4:c.7947+309A>C

Variant summary

Our verdict is Benign. The variant received -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
• 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]

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]

UQCC2 Gene-Disease associations (from GenCC):

• mitochondrial complex III deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex III deficiency nuclear type 7

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• 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 rank	MANE	Protein	UniProt
ITPR3	NM_002224.4	c.7947+309A>C		intron_variant	Intron 57 of 57	ENST00000605930.3	NP_002215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3	c.7947+309A>C		intron_variant	Intron 57 of 57	1	NM_002224.4	ENSP00000475177.1
UQCC2	ENST00000606961.1	n.3264T>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
UQCC2	ENST00000374231.8	c.*85T>G		3_prime_UTR_variant	Exon 5 of 5	3		ENSP00000363348.4
ITPR3	ENST00000374316.9	c.7947+309A>C		intron_variant	Intron 58 of 58	5		ENSP00000363435.4

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

GnomAD2 exomes AF: 0.146 AC: 7043 AN: 48332 AF XY: 0.142

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 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

African (AFR) AF: 0.0826 AC: 968 AN: 11722

American (AMR) AF: 0.161 AC: 2485 AN: 15468

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 2888 AN: 12720

East Asian (EAS) AF: 0.0892 AC: 2497 AN: 27992

South Asian (SAS) AF: 0.0771 AC: 3011 AN: 39064

European-Finnish (FIN) AF: 0.135 AC: 3592 AN: 26682

Middle Eastern (MID) AF: 0.202 AC: 370 AN: 1836

European-Non Finnish (NFE) AF: 0.198 AC: 48324 AN: 244478

Other (OTH) AF: 0.170 AC: 4038 AN: 23804

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

African (AFR) AF: 0.0844 AC: 3506 AN: 41548

American (AMR) AF: 0.174 AC: 2666 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 737 AN: 3470

East Asian (EAS) AF: 0.0457 AC: 237 AN: 5184

South Asian (SAS) AF: 0.0707 AC: 341 AN: 4826

European-Finnish (FIN) AF: 0.133 AC: 1414 AN: 10618

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.198 AC: 13436 AN: 67980

Other (OTH) AF: 0.178 AC: 377 AN: 2116

Alfa AF: 0.173 Hom.: 862

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
PhyloP100		0.17
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: rs2281919; hg19: chr6-33663171;