rs193920895

Variant names:

• chr16-48256612-G-T
• rs193920895
• NM_031490.5:c.471G>T

Variant summary

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

The NM_031490.5(LONP2):​c.471G>T​(p.Leu157Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000048 in 1,458,826 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: LONP2 NM_031490.5 missense, splice_region
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.34

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 rank	MANE	Protein	UniProt
LONP2	NM_031490.5	c.471G>T	p.Leu157Phe	missense_variant, splice_region_variant	Exon 3 of 15	ENST00000285737.9	NP_113678.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LONP2	ENST00000285737.9	c.471G>T	p.Leu157Phe	missense_variant, splice_region_variant	Exon 3 of 15	1	NM_031490.5	ENSP00000285737.4
LONP2	ENST00000535754.5	c.469-2006G>T		intron_variant	Intron 2 of 13	1		ENSP00000445426.1
LONP2	ENST00000566755.5	n.471G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 14	5		ENSP00000457841.1
LONP2	ENST00000416006.7	n.469-2006G>T		intron_variant	Intron 2 of 12	2		ENSP00000415983.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458826 Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 6 AN XY: 725700

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.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

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Science for Life laboratory, Karolinska Institutet

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.082	T
Polyphen		0.95	P
Vest4		0.61
MutPred		0.50		Loss of helix (P = 0.028);
MVP		0.77
MPC		0.96
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.48
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs193920895; hg19: chr16-48290523; COSMIC: COSV53524137;