6-32155030-A-T

Position:

• chr6-32155030-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005155.7(PPT2):​c.184A>T​(p.Thr62Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPT2 NM_005155.7 missense, splice_region
• Scores: Splicing: ADA: 0.03658
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

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]

PPT2-EGFL8 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19923857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPT2	NM_005155.7	c.184A>T	p.Thr62Ser	missense_variant, splice_region_variant	3/9	ENST00000324816.11	NP_005146.4
PPT2	NM_138717.3	c.202A>T	p.Thr68Ser	missense_variant, splice_region_variant	3/9		NP_619731.2
PPT2	NM_001204103.2	c.184A>T	p.Thr62Ser	missense_variant, splice_region_variant	3/9		NP_001191032.1
PPT2-EGFL8	NR_037861.1	n.598A>T		splice_region_variant, non_coding_transcript_exon_variant	3/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT2	ENST00000324816.11	c.184A>T	p.Thr62Ser	missense_variant, splice_region_variant	3/9	1	NM_005155.7	ENSP00000320528.6
PPT2-EGFL8	ENST00000422437.5	n.184A>T		splice_region_variant, non_coding_transcript_exon_variant	3/21	5		ENSP00000457534.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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 24, 2023

The c.202A>T (p.T68S) alteration is located in exon 3 (coding exon 3) of the PPT2 gene. This alteration results from a A to T substitution at nucleotide position 202, causing the threonine (T) at amino acid position 68 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.053	T;.;T;T;T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.82	T;T;.;T;.;.
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.50	.;.;N;N;N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.36	N;N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.66	T;T;T;T;T;T
Sift4G	Benign	0.58	T;T;T;T;T;T
Polyphen		0.0010	.;.;B;B;B;B
Vest4		0.097, 0.095, 0.094
MutPred		0.53		Gain of disorder (P = 0.0907);.;Gain of disorder (P = 0.0907);Gain of disorder (P = 0.0907);Gain of disorder (P = 0.0907);Gain of disorder (P = 0.0907);
MVP		0.29
MPC		0.70
ClinPred		0.76	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.037
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.090		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: chr6-32122807;