18-12028988-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014214.3(IMPA2):c.746C>A(p.Thr249Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: IMPA2 NM_014214.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IMPA2	NM_014214.3	c.746C>A	p.Thr249Asn	missense_variant	7/8	ENST00000269159.8
IMPA2	XM_011525659.4	c.698C>A	p.Thr233Asn	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IMPA2	ENST00000269159.8	c.746C>A	p.Thr249Asn	missense_variant	7/8	1	NM_014214.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Feb 28, 2024

The c.746C>A (p.T249N) alteration is located in exon 7 (coding exon 7) of the IMPA2 gene. This alteration results from a C to A substitution at nucleotide position 746, causing the threonine (T) at amino acid position 249 to be replaced by an asparagine (N). 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	0.59
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.33	T;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
Sift4G	Benign	0.30	T;D;T
Polyphen		0.68	.;P;.
Vest4		0.77
MutPred		0.50		.;Gain of sheet (P = 0.1945);.;
MVP		0.69
MPC		1.4
ClinPred		0.88	D
GERP RS		5.7
Varity_R		0.81
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-12028987;