12-122986118-C-G

Variant names:

• chr12-122986118-C-G
• rs1017607614
• NM_020845.3:c.3959G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_020845.3(PITPNM2):​c.3959G>C​(p.Arg1320Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000037 in 1,350,110 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: PITPNM2 NM_020845.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16938162).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITPNM2	NM_020845.3	c.3959G>C	p.Arg1320Pro	missense_variant	Exon 26 of 26	ENST00000320201.10	NP_065896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITPNM2	ENST00000320201.10	c.3959G>C	p.Arg1320Pro	missense_variant	Exon 26 of 26	5	NM_020845.3	ENSP00000322218.4
PITPNM2	ENST00000280562.9	c.3941G>C	p.Arg1314Pro	missense_variant	Exon 25 of 25	5		ENSP00000280562.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000370 AC: 5 AN: 1350110 Hom.: 0 Cov.: 31 AF XY: 0.00000301 AC XY: 2 AN XY: 665004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000532

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000178

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3959G>C (p.R1320P) alteration is located in exon 25 (coding exon 24) of the PITPNM2 gene. This alteration results from a G to C substitution at nucleotide position 3959, causing the arginine (R) at amino acid position 1320 to be replaced by a proline (P). 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	0.19
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.074	T;.;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	.;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;L
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.51	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.84	P;B;P
Vest4		0.19
MutPred		0.27		Loss of MoRF binding (P = 0.001);.;Loss of MoRF binding (P = 0.001);
MVP		0.54
MPC		2.5
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.29
gMVP		0.41

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: rs1017607614; hg19: chr12-123470665;