Genetic Variant ITPRIP:p.Lys342Asn (chr10-104315026-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001272013.2(ITPRIP):c.1026G>T(p.Lys342Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ITPRIP
NM_001272013.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.590

Variant links:

Genes affected

ITPRIP (HGNC:29370): (inositol 1,4,5-trisphosphate receptor interacting protein) This gene encodes a membrane-associated protein that binds the inositol 1,4,5-trisphosphate receptor (ITPR). The encoded protein enhances the sensitivity of ITPR to intracellular calcium signaling. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ITPRIP links:

Genome browser will be placed here

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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPRIP	NM_001272013.2 link	c.1026G>T	p.Lys342Asn	missense_variant	Exon 2 of 2	ENST00000337478.3	NP_001258942.1	Q8IWB1
ITPRIP	NM_001272012.2 link	c.1026G>T	p.Lys342Asn	missense_variant	Exon 2 of 2		NP_001258941.1	Q8IWB1
ITPRIP	NM_033397.4 link	c.1026G>T	p.Lys342Asn	missense_variant	Exon 3 of 3		NP_203755.1	Q8IWB1
ITPRIP	XM_005270257.3 link	c.1041G>T	p.Lys347Asn	missense_variant	Exon 2 of 2		XP_005270314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPRIP	ENST00000337478.3 link	c.1026G>T	p.Lys342Asn	missense_variant	Exon 2 of 2	1	NM_001272013.2	ENSP00000337178.1	Q8IWB1
ITPRIP	ENST00000278071.6 link	c.1026G>T	p.Lys342Asn	missense_variant	Exon 3 of 3	1		ENSP00000278071.2	Q8IWB1
ITPRIP	ENST00000358187.2 link	c.1026G>T	p.Lys342Asn	missense_variant	Exon 2 of 2	2		ENSP00000350915.2	Q8IWB1
ITPRIP	ENST00000647721.1 link	c.1026G>T	p.Lys342Asn	missense_variant	Exon 3 of 3			ENSP00000497746.1	Q8IWB1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251348

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727228

show subpopulations

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:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1026G>T (p.K342N) alteration is located in exon 3 (coding exon 1) of the ITPRIP gene. This alteration results from a G to T substitution at nucleotide position 1026, causing the lysine (K) at amino acid position 342 to be replaced by an asparagine (N). 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

Pathogenic

0.74

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T;T;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

T;.;.;.

M_CAP

Benign

0.053

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Pathogenic

3.1

M;M;M;M

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.3

N;N;N;.

REVEL

Benign

0.20

Sift

Uncertain

0.0040

D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;D;D;D

Vest4

0.54

MutPred

0.45

Loss of methylation at K342 (P = 0.0027);Loss of methylation at K342 (P = 0.0027);Loss of methylation at K342 (P = 0.0027);Loss of methylation at K342 (P = 0.0027);

MVP

0.19

MPC

0.87

ClinPred

0.88

GERP RS

4.1

Varity_R

0.39

gMVP

0.57

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over