chr6-32155909-C-T

Position:

• chr6-32155909-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_005155.7(PPT2):​c.472C>T​(p.Arg158Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PPT2 NM_005155.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPT2	NM_005155.7	c.472C>T	p.Arg158Trp	missense_variant	5/9	ENST00000324816.11	NP_005146.4
PPT2	NM_138717.3	c.490C>T	p.Arg164Trp	missense_variant	5/9		NP_619731.2
PPT2	NM_001204103.2	c.472C>T	p.Arg158Trp	missense_variant	5/9		NP_001191032.1
PPT2-EGFL8	NR_037861.1	n.886C>T		non_coding_transcript_exon_variant	5/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPT2	ENST00000324816.11	c.472C>T	p.Arg158Trp	missense_variant	5/9	1	NM_005155.7	ENSP00000320528.6
PPT2-EGFL8	ENST00000422437.5	n.472C>T		non_coding_transcript_exon_variant	5/21	5		ENSP00000457534.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251320 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461856 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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

Jul 14, 2021

The c.490C>T (p.R164W) alteration is located in exon 5 (coding exon 5) of the PPT2 gene. This alteration results from a C to T substitution at nucleotide position 490, causing the arginine (R) at amino acid position 164 to be replaced by a tryptophan (W). 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	0.67
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T;.;D;D;D;D;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.96	D;D;.;D;.;.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.7	.;.;L;L;L;L;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.017	D;D;D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;D;D;D;.
Vest4		0.58, 0.57, 0.57, 0.57
MutPred		0.68		Loss of helix (P = 0.0167);.;Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);.;
MVP		0.61
MPC		1.9
ClinPred		0.69	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs766967673; hg19: chr6-32123686;