12-122986679-G-C

Position:

• chr12-122986679-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_020845.3(PITPNM2):​c.3564C>G​(p.His1188Gln) 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. Variant has been reported in ClinVar 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: 2.53

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 2 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=0.29009157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITPNM2	NM_020845.3	c.3564C>G	p.His1188Gln	missense_variant	24/26	ENST00000320201.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITPNM2	ENST00000320201.10	c.3564C>G	p.His1188Gln	missense_variant	24/26	5	NM_020845.3	P3
PITPNM2	ENST00000280562.9	c.3546C>G	p.His1182Gln	missense_variant	23/25	5		A2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

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 22, 2023

The c.3564C>G (p.H1188Q) alteration is located in exon 23 (coding exon 22) of the PITPNM2 gene. This alteration results from a C to G substitution at nucleotide position 3564, causing the histidine (H) at amino acid position 1188 to be replaced by a glutamine (Q). 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	0.69
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.56	D;.;D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.69	N;.;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.7	D;N;D
REVEL	Uncertain	0.53
Sift	Benign	0.63	T;T;T
Sift4G	Benign	0.83	T;T;T
Polyphen		1.0	D;B;D
Vest4		0.54
MutPred		0.65		Gain of catalytic residue at H1183 (P = 0.0663);.;Gain of catalytic residue at H1183 (P = 0.0663);
MVP		0.77
MPC		2.2
ClinPred		0.74	D
GERP RS		3.1
Varity_R		0.32
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr12-123471226; COSMIC: COSV54903129; COSMIC: COSV54903129;