Variant 2-100295468-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198461.4(LONRF2):c.1562A>G(p.Lys521Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

LONRF2
NM_198461.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.05

Variant links:

Genes affected

LONRF2 (HGNC:24788): (LON peptidase N-terminal domain and ring finger 2) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

LONRF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.083355635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LONRF2	NM_198461.4 linkuse as main transcript	c.1562A>G	p.Lys521Arg	missense_variant	8/12	ENST00000393437.8	NP_940863.3	Q1L5Z9-1
LONRF2	NM_001371783.1 linkuse as main transcript	c.833A>G	p.Lys278Arg	missense_variant	9/13		NP_001358712.1
LONRF2	XM_047443537.1 linkuse as main transcript	c.833A>G	p.Lys278Arg	missense_variant	8/12		XP_047299493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LONRF2	ENST00000393437.8 linkuse as main transcript	c.1562A>G	p.Lys521Arg	missense_variant	8/12	5	NM_198461.4	ENSP00000377086.3		Q1L5Z9-1
LONRF2	ENST00000409647.1 linkuse as main transcript	c.833A>G	p.Lys278Arg	missense_variant	8/12	2		ENSP00000386823.1		Q1L5Z9-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251278

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461562

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727082

show subpopulations

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:

0.000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

The c.1562A>G (p.K521R) alteration is located in exon 8 (coding exon 8) of the LONRF2 gene. This alteration results from a A to G substitution at nucleotide position 1562, causing the lysine (K) at amino acid position 521 to be replaced by an arginine (R). 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

0.10

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.011

T;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.083

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.21

Sift

Benign

0.47

T;T

Sift4G

Benign

0.54

T;T

Polyphen

0.33

B;.

Vest4

0.11

MutPred

0.39

Loss of ubiquitination at K521 (P = 0.0074);.;

MVP

0.62

MPC

0.63

ClinPred

0.086

GERP RS

1.6

Varity_R

0.055

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over