6-33694518-G-C

Variant names:

• chr6-33694518-G-C
• rs3227
• NM_002224.4:c.7786-406G>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.7786-406G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 250,844 control chromosomes in the GnomAD database, including 30,604 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 0.42 (15673 hom., cov: 32)
  • Exomes 𝑓: 0.54 (14931 hom.)
• Consequence: ITPR3 NM_002224.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.294
• Publications: 19 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 (EAS) allele frequency at 95% confidence interval = 0.842 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.7786-406G>C		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.7786-406G>C		intron	N/A	ENSP00000475177.1
	UQCC2	ENST00000606961.1	TSL:6	n.4140C>G		non_coding_transcript_exon	Exon 1 of 1
	ITPR3	ENST00000374316.9	TSL:5	c.7786-406G>C		intron	N/A	ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63413 AN: 151966 Hom.: 15675 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.864

Gnomad SAS AF: 0.761

Gnomad FIN AF: 0.607

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.397

GnomAD4 exome AF: 0.536 AC: 52900 AN: 98760 Hom.: 14931 Cov.: 0 AF XY: 0.563 AC XY: 30075 AN XY: 53458

African (AFR) AF: 0.177 AC: 186 AN: 1052

American (AMR) AF: 0.576 AC: 1250 AN: 2170

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 1081 AN: 2232

East Asian (EAS) AF: 0.844 AC: 1047 AN: 1240

South Asian (SAS) AF: 0.739 AC: 14751 AN: 19972

European-Finnish (FIN) AF: 0.579 AC: 3567 AN: 6162

Middle Eastern (MID) AF: 0.502 AC: 213 AN: 424

European-Non Finnish (NFE) AF: 0.468 AC: 28202 AN: 60264

Other (OTH) AF: 0.496 AC: 2603 AN: 5244

GnomAD4 genome AF: 0.417 AC: 63424 AN: 152084 Hom.: 15673 Cov.: 32 AF XY: 0.437 AC XY: 32460 AN XY: 74342

African (AFR) AF: 0.179 AC: 7440 AN: 41506

American (AMR) AF: 0.518 AC: 7916 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1630 AN: 3470

East Asian (EAS) AF: 0.864 AC: 4439 AN: 5140

South Asian (SAS) AF: 0.761 AC: 3675 AN: 4828

European-Finnish (FIN) AF: 0.607 AC: 6417 AN: 10580

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.448 AC: 30470 AN: 67960

Other (OTH) AF: 0.400 AC: 845 AN: 2110

Alfa AF: 0.291 Hom.: 832

Bravo AF: 0.396

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.9
DANN	Benign	0.43
PhyloP100		0.29
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: rs3227; hg19: chr6-33662295;