chr6-32162817-G-C

Position:

• chr6-32162817-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005155.7(PPT2):​c.776G>C​(p.Arg259Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPT2 NM_005155.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38

Genes affected

PPT2 (HGNC:9326): (palmitoyl-protein thioesterase 2) This gene encodes a member of the palmitoyl-protein thioesterase family. The encoded glycosylated lysosomal protein has palmitoyl-CoA hydrolase activity in vitro, but does not hydrolyze palmitate from cysteine residues in proteins. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream EGFL8 (EGF-like-domain, multiple 8) gene. [provided by RefSeq, Feb 2011]

PPT2-EGFL8 (HGNC:48343): (PPT2-EGFL8 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring PPT2 (palmitoyl-protein thioesterase 2) and EGFL8 (EGF-like-domain, multiple 8) genes located in the major histocompatibility complex class III region of chromosome 6. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPT2	NM_005155.7	c.776G>C	p.Arg259Pro	missense_variant	9/9	ENST00000324816.11	NP_005146.4
PPT2	NM_138717.3	c.794G>C	p.Arg265Pro	missense_variant	9/9		NP_619731.2
PPT2	NM_001204103.2	c.776G>C	p.Arg259Pro	missense_variant	9/9		NP_001191032.1
PPT2-EGFL8	NR_037861.1	n.1179+195G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT2	ENST00000324816.11	c.776G>C	p.Arg259Pro	missense_variant	9/9	1	NM_005155.7	ENSP00000320528.6
PPT2-EGFL8	ENST00000422437.5	n.765+195G>C		intron_variant		5		ENSP00000457534.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Jun 12, 2023

The c.794G>C (p.R265P) alteration is located in exon 9 (coding exon 9) of the PPT2 gene. This alteration results from a G to C substitution at nucleotide position 794, causing the arginine (R) at amino acid position 265 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	.;D;D;D;D
Eigen	Benign	0.034
Eigen_PC	Benign	0.048
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.93	D;.;D;.;.
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.52	D;D;D;D;D
MetaSVM	Uncertain	-0.0065	T
MutationAssessor	Benign	1.4	.;L;L;L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	N;N;N;N;N
REVEL	Uncertain	0.63
Sift	Benign	0.15	T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.89	.;P;P;P;P
Vest4		0.49
MutPred		0.52		.;Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP		0.70
MPC		1.4
ClinPred		0.67	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr6-32130594;