12-122986062-G-C

Position:

• chr12-122986062-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_020845.3(PITPNM2):​c.4015C>G​(p.Arg1339Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1339C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PITPNM2 NM_020845.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

Genes affected

PITPNM2 (HGNC:21044): (phosphatidylinositol transfer protein membrane associated 2) PITPNM2 belongs to a family of membrane-associated phosphatidylinositol transfer domain-containing proteins that share homology with the Drosophila retinal degeneration B (rdgB) protein (Ocaka et al., 2005 [PubMed 15627748]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PITPNM2
• BP4: Computational evidence support a benign effect (MetaRNN=0.25152525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITPNM2	NM_020845.3	c.4015C>G	p.Arg1339Gly	missense_variant	26/26	ENST00000320201.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITPNM2	ENST00000320201.10	c.4015C>G	p.Arg1339Gly	missense_variant	26/26	5	NM_020845.3	P3
PITPNM2	ENST00000280562.9	c.3997C>G	p.Arg1333Gly	missense_variant	25/25	5		A2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

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

Sep 20, 2023

The c.4015C>G (p.R1339G) alteration is located in exon 25 (coding exon 24) of the PITPNM2 gene. This alteration results from a C to G substitution at nucleotide position 4015, causing the arginine (R) at amino acid position 1339 to be replaced by a glycine (G). 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	0.15
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L;.;L
MutationTaster	Benign	0.66	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.91	P;D;P
Vest4		0.36
MutPred		0.34		Gain of catalytic residue at R1339 (P = 4e-04);.;Gain of catalytic residue at R1339 (P = 4e-04);
MVP		0.093
MPC		2.4
ClinPred		0.86	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.36

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: chr12-123470609;