12-26400226-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002223.4(ITPR2):​c.7432A>G​(p.Thr2478Ala) 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. 14/22 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. T2478M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

ITPR2
NM_002223.4 missense

Scores

5
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.06

Publications

0 publications found
Variant links:
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]
ITPR2 Gene-Disease associations (from GenCC):
  • isolated anhidrosis with normal sweat glands
    Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.21654701).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ITPR2NM_002223.4 linkc.7432A>G p.Thr2478Ala missense_variant Exon 53 of 57 ENST00000381340.8 NP_002214.2 Q14571-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ITPR2ENST00000381340.8 linkc.7432A>G p.Thr2478Ala missense_variant Exon 53 of 57 1 NM_002223.4 ENSP00000370744.3 Q14571-1
ITPR2ENST00000451599.6 linkn.*1951A>G non_coding_transcript_exon_variant Exon 16 of 18 1 ENSP00000408287.2 H7C2X9
ITPR2ENST00000451599.6 linkn.*1951A>G 3_prime_UTR_variant Exon 16 of 18 1 ENSP00000408287.2 H7C2X9
ENSG00000255968ENST00000535324.1 linkn.53-431T>C intron_variant Intron 1 of 5 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1439152
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
715866
African (AFR)
AF:
0.00
AC:
0
AN:
33142
American (AMR)
AF:
0.00
AC:
0
AN:
43810
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25624
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39250
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82078
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52450
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5692
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1097790
Other (OTH)
AF:
0.00
AC:
0
AN:
59316
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.076
D
BayesDel_noAF
Benign
-0.13
CADD
Benign
19
DANN
Benign
0.85
DEOGEN2
Uncertain
0.51
D
Eigen
Benign
-0.82
Eigen_PC
Benign
-0.58
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.75
T
M_CAP
Benign
0.078
D
MetaRNN
Benign
0.22
T
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Benign
-0.10
N
PhyloP100
3.1
PrimateAI
Benign
0.41
T
PROVEAN
Benign
0.29
N
REVEL
Uncertain
0.35
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.25
MutPred
0.49
Gain of catalytic residue at T2481 (P = 0.0195);
MVP
0.48
MPC
0.78
ClinPred
0.28
T
GERP RS
2.2
Varity_R
0.028
gMVP
0.40
Mutation Taster
=85/15
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

Publications

Other links and lift over

dbSNP: rs1940129738; hg19: chr12-26553159; API