Genetic Variant PITPNM2:p.Arg1320Pro (chr12-122986118-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52

Publications

0 publications found

Variant links:

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]

PITPNM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 link	c.3959G>C	p.Arg1320Pro	missense_variant	Exon 26 of 26	ENST00000320201.10	NP_065896.1	Q9BZ72-1Q9UF51

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITPNM2	ENST00000320201.10 link	c.3959G>C	p.Arg1320Pro	missense_variant	Exon 26 of 26	5	NM_020845.3	ENSP00000322218.4		Q9BZ72-1
PITPNM2	ENST00000280562.9 link	c.3941G>C	p.Arg1314Pro	missense_variant	Exon 25 of 25	5		ENSP00000280562.5		Q9BZ72-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000370

AC:

AN:

1350110

Hom.:

Cov.:

AF XY:

0.00000301

AC XY:

AN XY:

665004

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27746

American (AMR)

AF:

0.00

AC:

AN:

30746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23716

East Asian (EAS)

AF:

0.00

AC:

AN:

32700

South Asian (SAS)

AF:

0.0000532

AC:

AN:

75202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4442

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1064998

Other (OTH)

AF:

0.0000178

AC:

AN:

56168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.074

T;.;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

.;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;.;L

PhyloP100

2.5

PrimateAI

Pathogenic

0.79

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

GERP RS

4.8

Varity_R

0.29

gMVP

0.41

Mutation Taster

=57/43

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over