12-26792480-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002223.4(ITPR2):c.93-2253G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 151,832 control chromosomes in the GnomAD database, including 67,780 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 0.94 (67780 hom., cov: 27)
• Consequence: ITPR2 NM_002223.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0750

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR2	NM_002223.4	c.93-2253G>A		intron_variant		ENST00000381340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR2	ENST00000381340.8	c.93-2253G>A		intron_variant		1	NM_002223.4	P1
ITPR2	ENST00000242737.5	c.93-2253G>A		intron_variant		1
ITPR2	ENST00000545235.1	c.92+40210G>A		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.944 AC: 143216 AN: 151714 Hom.: 67723 Cov.: 27

Gnomad AFR AF: 0.984

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.974

Gnomad ASJ AF: 0.933

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.958

Gnomad FIN AF: 0.869

Gnomad MID AF: 0.924

Gnomad NFE AF: 0.920

Gnomad OTH AF: 0.946

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

GnomAD4 genome AF: 0.944 AC: 143332 AN: 151832 Hom.: 67780 Cov.: 27 AF XY: 0.942 AC XY: 69932 AN XY: 74202

Gnomad4 AFR AF: 0.984

Gnomad4 AMR AF: 0.974

Gnomad4 ASJ AF: 0.933

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.957

Gnomad4 FIN AF: 0.869

Gnomad4 NFE AF: 0.920

Gnomad4 OTH AF: 0.947

Alfa AF: 0.929 Hom.: 84844

Bravo AF: 0.953

Asia WGS AF: 0.978 AC: 3400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	3.7
Dann	Benign	0.17

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

Other links and lift over

dbSNP: rs2122268; hg19: chr12-26945413;