6-32162909-C-G

Position:

• chr6-32162909-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005155.7(PPT2):​c.868C>G​(p.Arg290Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PPT2 NM_005155.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26577076).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPT2	NM_005155.7	c.868C>G	p.Arg290Gly	missense_variant	9/9	ENST00000324816.11	NP_005146.4
PPT2	NM_138717.3	c.886C>G	p.Arg296Gly	missense_variant	9/9		NP_619731.2
PPT2	NM_001204103.2	c.868C>G	p.Arg290Gly	missense_variant	9/9		NP_001191032.1
PPT2-EGFL8	NR_037861.1	n.1179+287C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT2	ENST00000324816.11	c.868C>G	p.Arg290Gly	missense_variant	9/9	1	NM_005155.7	ENSP00000320528.6
PPT2-EGFL8	ENST00000422437.5	n.765+287C>G		intron_variant		5		ENSP00000457534.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727222

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

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

Mar 28, 2024

The c.886C>G (p.R296G) alteration is located in exon 9 (coding exon 9) of the PPT2 gene. This alteration results from a C to G substitution at nucleotide position 886, causing the arginine (R) at amino acid position 296 to be replaced by a glycine (G). 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	0.30
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;T;T;T;T
Eigen	Benign	0.0070
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.86	D;.;D;.;.
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.4	.;L;L;L;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.42	T;T;T;T;T
Sift4G	Benign	0.42	T;T;T;T;T
Polyphen		0.36	.;B;B;B;B
Vest4		0.41
MutPred		0.41		.;Loss of stability (P = 0.0348);Loss of stability (P = 0.0348);Loss of stability (P = 0.0348);Loss of stability (P = 0.0348);
MVP		0.63
MPC		1.2
ClinPred		0.58	D
GERP RS		5.6
Varity_R		0.22
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs144778647; hg19: chr6-32130686;