18-12028045-C-T

Variant names:

• chr18-12028045-C-T
• rs767421989
• NM_014214.3:c.493C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014214.3(IMPA2):​c.493C>T​(p.Leu165Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,100 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L165V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IMPA2 NM_014214.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17
• Publications: 0 publications found

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]

ENSG00000293189 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014214.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPA2	NM_014214.3	MANE Select	c.493C>T	p.Leu165Phe	missense splice_region	Exon 6 of 8	NP_055029.1	O14732-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IMPA2	ENST00000269159.8	TSL:1 MANE Select	c.493C>T	p.Leu165Phe	missense splice_region	Exon 6 of 8	ENSP00000269159.3	O14732-1
	IMPA2	ENST00000588927.5	TSL:5	c.-75C>T		splice_region	Exon 6 of 8	ENSP00000464767.1	K7EII9
	IMPA2	ENST00000589238.5	TSL:3	c.-75C>T		splice_region	Exon 6 of 8	ENSP00000465416.1	K7EII9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250826 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456100 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724896

African (AFR) AF: 0.00 AC: 0 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107110

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.19
Sift	Benign	0.047	D
Sift4G	Benign	0.062	T
Polyphen		0.54	P
Vest4		0.29
MutPred		0.71		Gain of catalytic residue at L165 (P = 0.1106)
MVP		0.63
MPC		0.81
ClinPred		0.64	D
GERP RS		5.0
Varity_R		0.29
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs767421989; hg19: chr18-12028044; COSMIC: COSV106365659; COSMIC: COSV106365659;