18-12028978-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014214.3(IMPA2):c.736G>A(p.Val246Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000253 in 1,461,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: IMPA2 NM_014214.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.00

Genes affected

IMPA2 (HGNC:6051): (inositol monophosphatase 2) This locus encodes an inositol monophosphatase. The encoded protein catalyzes the dephosphoylration of inositol monophosphate and plays an important role in phosphatidylinositol signaling. This locus may be associated with susceptibility to bipolar disorder. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IMPA2	NM_014214.3	c.736G>A	p.Val246Met	missense_variant	7/8	ENST00000269159.8
IMPA2	XM_011525659.4	c.688G>A	p.Val230Met	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IMPA2	ENST00000269159.8	c.736G>A	p.Val246Met	missense_variant	7/8	1	NM_014214.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250754 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135552

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461334 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727004

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.000296 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2023

The c.736G>A (p.V246M) alteration is located in exon 7 (coding exon 7) of the IMPA2 gene. This alteration results from a G to A substitution at nucleotide position 736, causing the valine (V) at amino acid position 246 to be replaced by a methionine (M). 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	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
Sift4G	Uncertain	0.016	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.78
MutPred		0.79		.;Loss of catalytic residue at V246 (P = 0.0348);.;
MVP		0.67
MPC		1.3
ClinPred		0.68	D
GERP RS		5.7
Varity_R		0.68
gMVP		0.72

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: rs757011831; hg19: chr18-12028977;