16-48351755-G-A

Variant summary

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

The NM_031490.5(LONP2):c.2512G>A(p.Gly838Ser) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: LONP2 NM_031490.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

LONP2 (HGNC:20598): (lon peptidase 2, peroxisomal) In human, peroxisomes function primarily to catalyze fatty acid beta-oxidation and, as a by-product, produce hydrogen peroxide and superoxide. The protein encoded by this gene is an ATP-dependent protease that likely plays a role in maintaining overall peroxisome homeostasis as well as proteolytically degrading peroxisomal proteins damaged by oxidation. The protein has an N-terminal Lon N substrate recognition domain, an ATPase domain, a proteolytic domain, and, in some isoforms, a C-terminal peroxisome targeting sequence. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2017]

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	UniProt
LONP2	NM_031490.5	c.2512G>A	p.Gly838Ser	missense_variant	15/15	ENST00000285737.9
LONP2	NM_001348078.2	c.2512G>A	p.Gly838Ser	missense_variant	15/17
LONP2	NM_001300948.3	c.2380G>A	p.Gly794Ser	missense_variant	14/14
LONP2	XM_047434738.1	c.2512G>A	p.Gly838Ser	missense_variant	15/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LONP2	ENST00000285737.9	c.2512G>A	p.Gly838Ser	missense_variant	15/15	1	NM_031490.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Aug 02, 2023

The c.2512G>A (p.G838S) alteration is located in exon 15 (coding exon 15) of the LONP2 gene. This alteration results from a G to A substitution at nucleotide position 2512, causing the glycine (G) at amino acid position 838 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	0.16
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Benign	0.049	T;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		1.0	D;.
Vest4		0.61
MutPred		0.46		Gain of relative solvent accessibility (P = 0.0522);.;
MVP		0.73
MPC		1.8
ClinPred		0.96	D
GERP RS		6.1
Varity_R		0.44
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: -3

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: chr16-48385666;