rs16930692

Variant names:

• chr12-26433073-A-C
• rs16930692
• NM_002223.4:c.6769+3148T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002223.4(ITPR2):​c.6769+3148T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 152,302 control chromosomes in the GnomAD database, including 240 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 0.047 (240 hom., cov: 32)
• Consequence: ITPR2 NM_002223.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.478
• Publications: 2 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR2	NM_002223.4	c.6769+3148T>G		intron_variant	Intron 48 of 56	ENST00000381340.8	NP_002214.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR2	ENST00000381340.8	c.6769+3148T>G		intron_variant	Intron 48 of 56	1	NM_002223.4	ENSP00000370744.3
ITPR2	ENST00000451599.6	n.*1288+3148T>G		intron_variant	Intron 11 of 17	1		ENSP00000408287.2

Frequencies

GnomAD3 genomes AF: 0.0469 AC: 7140 AN: 152184 Hom.: 241 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0357

Gnomad ASJ AF: 0.0893

Gnomad EAS AF: 0.0344

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.0532

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0602

Gnomad OTH AF: 0.0512

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0468 AC: 7132 AN: 152302 Hom.: 240 Cov.: 32 AF XY: 0.0485 AC XY: 3615 AN XY: 74466

African (AFR) AF: 0.0109 AC: 452 AN: 41578

American (AMR) AF: 0.0356 AC: 545 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0893 AC: 310 AN: 3470

East Asian (EAS) AF: 0.0343 AC: 178 AN: 5190

South Asian (SAS) AF: 0.174 AC: 838 AN: 4824

European-Finnish (FIN) AF: 0.0532 AC: 564 AN: 10604

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0602 AC: 4096 AN: 68024

Other (OTH) AF: 0.0497 AC: 105 AN: 2112

Alfa AF: 0.0468 Hom.: 27

Bravo AF: 0.0404

Asia WGS AF: 0.104 AC: 359 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.9
DANN	Benign	0.50
PhyloP100		0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16930692; hg19: chr12-26586006;