Genetic Variant NM_002223.4: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:

ENSG00000255968 (HGNC:58268):

ENSG00000255968 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR2	NM_002223.4 link	c.*2786C>A		3_prime_UTR_variant	Exon 57 of 57	ENST00000381340.8	NP_002214.2	Q14571-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPR2	ENST00000381340.8 link	c.*2786C>A	3_prime_UTR_variant	Exon 57 of 57	1	NM_002223.4	ENSP00000370744.3	Q14571-1
ENSG00000255968	ENST00000535324.1 link	n.52+17607G>T	intron_variant	Intron 1 of 5	3
ENSG00000256185	ENST00000537724.1 link	n.126+214C>A	intron_variant	Intron 1 of 1	3

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

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 v4.3

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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NM_002223.4:c.*2786C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over