chr12-26387528-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_002223.4(ITPR2):c.7763A>G(p.Asn2588Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,613,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000072 ( 0 hom. )
Consequence
ITPR2
NM_002223.4 missense
NM_002223.4 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 2.34
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, ITPR2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.34854382).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITPR2 | NM_002223.4 | c.7763A>G | p.Asn2588Ser | missense_variant | 55/57 | ENST00000381340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITPR2 | ENST00000381340.8 | c.7763A>G | p.Asn2588Ser | missense_variant | 55/57 | 1 | NM_002223.4 | P1 | |
ENST00000535324.1 | n.53-13129T>C | intron_variant, non_coding_transcript_variant | 3 | ||||||
ITPR2 | ENST00000451599.6 | downstream_gene_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152242Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000642 AC: 16AN: 249200Hom.: 0 AF XY: 0.0000592 AC XY: 8AN XY: 135216
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GnomAD4 exome AF: 0.0000718 AC: 105AN: 1461484Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42AN XY: 727066
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74388
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 12, 2023 | The c.7763A>G (p.N2588S) alteration is located in exon 55 (coding exon 55) of the ITPR2 gene. This alteration results from a A to G substitution at nucleotide position 7763, causing the asparagine (N) at amino acid position 2588 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at