Genetic Variant ITPR2:c.*2786C>A (chr12-26336611-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002223.4(ITPR2):c.*2786C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 152,022 control chromosomes in the GnomAD database, including 37,050 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.69 ( 37050 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

ITPR2
NM_002223.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.305

Publications

34 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

ITPR2 links:

ITPR2-AS2 (HGNC:58268):

ITPR2-AS2 links:

ENSG00000256185 (HGNC:):

ENSG00000256185 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.804 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002223.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ITPR2	NM_002223.4	MANE Select	c.*2786C>A	3_prime_UTR	Exon 57 of 57	NP_002214.2
ITPR2	NM_001414174.1		c.*2786C>A	3_prime_UTR	Exon 57 of 57	NP_001401103.1
ITPR2	NM_001414175.1		c.*2786C>A	3_prime_UTR	Exon 55 of 55	NP_001401104.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ITPR2	ENST00000381340.8	TSL:1 MANE Select	c.*2786C>A	3_prime_UTR	Exon 57 of 57	ENSP00000370744.3
ITPR2-AS2	ENST00000535324.1	TSL:3	n.52+17607G>T	intron	N/A
ENSG00000256185	ENST00000537724.1	TSL:3	n.126+214C>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.694

AC:

105440

AN:

151904

Hom.:

37001

Cov.:

show subpopulations

Gnomad AFR

AF:

0.688

Gnomad AMI

AF:

0.878

Gnomad AMR

AF:

0.587

Gnomad ASJ

AF:

0.794

Gnomad EAS

AF:

0.482

Gnomad SAS

AF:

0.824

Gnomad FIN

AF:

0.652

Gnomad MID

AF:

0.810

Gnomad NFE

AF:

0.726

Gnomad OTH

AF:

0.728

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.694

AC:

105543

AN:

152022

Hom.:

37050

Cov.:

AF XY:

0.691

AC XY:

51362

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.688

AC:

28533

AN:

41446

American (AMR)

AF:

0.586

AC:

8943

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.794

AC:

2755

AN:

3470

East Asian (EAS)

AF:

0.483

AC:

2498

AN:

5174

South Asian (SAS)

AF:

0.825

AC:

3981

AN:

4824

European-Finnish (FIN)

AF:

0.652

AC:

6880

AN:

10558

Middle Eastern (MID)

AF:

0.806

AC:

237

AN:

294

European-Non Finnish (NFE)

AF:

0.726

AC:

49374

AN:

67982

Other (OTH)

AF:

0.730

AC:

1541

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1620

3240

4859

6479

8099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

826

1652

2478

3304

4130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.720

Hom.:

66319

Bravo

AF:

0.688

Asia WGS

AF:

0.697

AC:

2402

AN:

3450

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.6

(source)

DANN

Benign

0.57

PhyloP100

0.30

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over