12-122986284-G-A

Variant names:

• chr12-122986284-G-A
• rs746643450
• NM_020845.3:c.3793C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_020845.3(PITPNM2):​c.3793C>T​(p.Arg1265Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000067 in 1,583,042 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1265H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: PITPNM2 NM_020845.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21498093).
• BS2: High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020845.3. 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
	PITPNM2	NM_020845.3	MANE Select	c.3793C>T	p.Arg1265Cys	missense	Exon 26 of 26	NP_065896.1	Q9BZ72-1
	PITPNM2	NM_001384660.1		c.3970C>T	p.Arg1324Cys	missense	Exon 26 of 26	NP_001371589.1
	PITPNM2	NM_001300801.2		c.3775C>T	p.Arg1259Cys	missense	Exon 26 of 26	NP_001287730.1	Q9BZ72-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITPNM2	ENST00000320201.10	TSL:5 MANE Select	c.3793C>T	p.Arg1265Cys	missense	Exon 26 of 26	ENSP00000322218.4	Q9BZ72-1
	PITPNM2	ENST00000876870.1		c.3793C>T	p.Arg1265Cys	missense	Exon 25 of 25	ENSP00000546929.1
	PITPNM2	ENST00000280562.9	TSL:5	c.3775C>T	p.Arg1259Cys	missense	Exon 25 of 25	ENSP00000280562.5	Q9BZ72-2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000259 AC: 5 AN: 193350 AF XY: 0.0000375

Gnomad AFR exome AF: 0.0000863

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: 0.0000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000685 AC: 98 AN: 1430810 Hom.: 0 Cov.: 31 AF XY: 0.0000690 AC XY: 49 AN XY: 709744

African (AFR) AF: 0.0000303 AC: 1 AN: 32952

American (AMR) AF: 0.00 AC: 0 AN: 39950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25302

East Asian (EAS) AF: 0.00 AC: 0 AN: 38636

South Asian (SAS) AF: 0.000146 AC: 12 AN: 82274

European-Finnish (FIN) AF: 0.0000220 AC: 1 AN: 45498

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5704

European-Non Finnish (NFE) AF: 0.0000736 AC: 81 AN: 1101242

Other (OTH) AF: 0.0000169 AC: 1 AN: 59252

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74362

African (AFR) AF: 0.0000723 AC: 3 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000435 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000849 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.23
MutPred		0.37		Gain of catalytic residue at T1267 (P = 0.0012)
MVP		0.082
MPC		2.2
ClinPred		0.43	T
GERP RS		3.8
Varity_R		0.21
gMVP		0.35
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs746643450; hg19: chr12-123470831;