12-26398927-T-C

Position:

• chr12-26398927-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_002223.4(ITPR2):​c.7645A>G​(p.Ser2549Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ITPR2 NM_002223.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.96

Genes affected

ITPR2 (HGNC:6181): (inositol 1,4,5-trisphosphate receptor type 2) The protein encoded by this gene belongs to the inositol 1,4,5-triphosphate receptor family, whose members are second messenger intracellular calcium release channels. These proteins mediate a rise in cytoplasmic calcium in response to receptor activated production of inositol triphosphate. Inositol triphosphate receptor-mediated signaling is involved in many processes including cell migration, cell division, smooth muscle contraction, and neuronal signaling. This protein is a type 2 receptor that consists of a cytoplasmic amino-terminus that binds inositol triphosphate, six membrane-spanning helices that contribute to the ion pore, and a short cytoplasmic carboxy-terminus. A mutation in this gene has been associated with anhidrosis, suggesting that intracellular calcium release mediated by this protein is required for eccrine sweat production. [provided by RefSeq, Apr 2015]

ENSG00000255968 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ITPR2. . Gene score misZ 3.7096 (greater than the threshold 3.09). Trascript score misZ 4.4686 (greater than threshold 3.09). GenCC has associacion of gene with isolated anhidrosis with normal sweat glands.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR2	NM_002223.4	c.7645A>G	p.Ser2549Gly	missense_variant	54/57	ENST00000381340.8	NP_002214.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR2	ENST00000381340.8	c.7645A>G	p.Ser2549Gly	missense_variant	54/57	1	NM_002223.4	ENSP00000370744.3
ITPR2	ENST00000451599.6	n.*2164A>G		non_coding_transcript_exon_variant	17/18	1		ENSP00000408287.2
ITPR2	ENST00000451599.6	n.*2164A>G		3_prime_UTR_variant	17/18	1		ENSP00000408287.2
ENSG00000255968	ENST00000535324.1	n.53-1730T>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459646 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.7645A>G (p.S2549G) alteration is located in exon 54 (coding exon 54) of the ITPR2 gene. This alteration results from a A to G substitution at nucleotide position 7645, causing the serine (S) at amino acid position 2549 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.76
MutPred		0.30		Gain of catalytic residue at A2545 (P = 0);
MVP		0.92
MPC		1.2
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-26551860;