rs2229642

Variant names:

• chr6-33691695-C-A
• rs2229642
• NM_002224.4:c.7306C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-33691695-C-A
• chr6-33691695-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002224.4(ITPR3):​c.7306C>A​(p.Leu2436Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2436V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ITPR3 NM_002224.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.687
• Publications: 49 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08984253).

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.7306C>A	p.Leu2436Ile	missense	Exon 53 of 58	NP_002215.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR3	ENST00000605930.3	TSL:1 MANE Select	c.7306C>A	p.Leu2436Ile	missense	Exon 53 of 58	ENSP00000475177.1
	ITPR3	ENST00000374316.9	TSL:5	c.7306C>A	p.Leu2436Ile	missense	Exon 54 of 59	ENSP00000363435.4
	ITPR3	ENST00000931640.1		c.7276C>A	p.Leu2426Ile	missense	Exon 53 of 58	ENSP00000601699.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.1
DANN	Benign	0.33
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.045	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.85	L
PhyloP100		0.69
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.067
Sift	Benign	0.56	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.073
MutPred		0.34		Loss of disorder (P = 0.0848)
MVP		0.61
MPC		0.75
ClinPred		0.024	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.16
Mutation Taster		=100/0	polymorphism

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: rs2229642; hg19: chr6-33659472;