rs200691111

Variant names:

• chr12-26340222-G-A
• rs200691111
• NM_002223.4:c.7964C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-26340222-G-A
• chr12-26340222-G-C
• chr12-26340222-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002223.4(ITPR2):​c.7964C>T​(p.Ser2655Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,610,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ITPR2 NM_002223.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

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]

ENSG00000255968 (HGNC:58268):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053634644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR2	NM_002223.4	c.7964C>T	p.Ser2655Leu	missense_variant	Exon 56 of 57	ENST00000381340.8	NP_002214.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR2	ENST00000381340.8	c.7964C>T	p.Ser2655Leu	missense_variant	Exon 56 of 57	1	NM_002223.4	ENSP00000370744.3
ENSG00000255968	ENST00000535324.1	n.52+21218G>A		intron_variant	Intron 1 of 5	3

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000285 AC: 70 AN: 245880 Hom.: 0 AF XY: 0.000337 AC XY: 45 AN XY: 133402

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.000285

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000139 AC: 203 AN: 1458012 Hom.: 0 Cov.: 31 AF XY: 0.000145 AC XY: 105 AN XY: 725108

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00157

Gnomad4 NFE exome AF: 0.0000919

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74426

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000273 AC: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7964C>T (p.S2655L) alteration is located in exon 56 (coding exon 56) of the ITPR2 gene. This alteration results from a C to T substitution at nucleotide position 7964, causing the serine (S) at amino acid position 2655 to be replaced by a leucine (L). 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	Benign	0.082
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.0023
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.090
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.020	D
Polyphen		0.35	B
Vest4		0.40
MutPred		0.31		Loss of phosphorylation at S2655 (P = 0.0497);
MVP		0.49
MPC		0.74
ClinPred		0.11	T
GERP RS		5.6
Varity_R		0.25
gMVP		0.25

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: rs200691111; hg19: chr12-26493155; COSMIC: COSV104430481; COSMIC: COSV104430481;