20-64084065-G-A

Position:

chr20-64084065-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001353425.2(LKAAEAR1):c.155C>T(p.Ala52Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000422 in 1,497,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

LKAAEAR1
NM_001353425.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.283

Variant links:

Genes affected

LKAAEAR1 (HGNC:33718): (LKAAEAR motif containing 1)

LKAAEAR1 links:

OPRL1 (HGNC:8155): (opioid related nociceptin receptor 1) The protein encoded by this gene is a member of the 7 transmembrane-spanning G protein-coupled receptor family, and functions as a receptor for the endogenous, opioid-related neuropeptide, nociceptin/orphanin FQ. This receptor-ligand system modulates a variety of biological functions and neurobehavior, including stress responses and anxiety behavior, learning and memory, locomotor activity, and inflammatory and immune responses. A promoter region between this gene and the 5'-adjacent RGS19 (regulator of G-protein signaling 19) gene on the opposite strand functions bi-directionally as a core-promoter for both genes, suggesting co-operative transcriptional regulation of these two functionally related genes. Alternatively spliced transcript variants have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Dec 2017]

OPRL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008240789).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LKAAEAR1	NM_001353425.2 link	c.155C>T	p.Ala52Val	missense_variant	1/3	ENST00000302096.5	NP_001340354.1
OPRL1	NM_182647.4 link	c.-185+3713G>A		intron_variant		ENST00000336866.7	NP_872588.1	P41146-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LKAAEAR1	ENST00000302096.5 link	c.155C>T	p.Ala52Val	missense_variant	1/3	2	NM_001353425.2	ENSP00000302763.4		Q8TD35-1
OPRL1	ENST00000336866.7 link	c.-185+3713G>A		intron_variant		5	NM_182647.4	ENSP00000336843.2		P41146-1

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000367

AC:

AN:

98202

Hom.:

AF XY:

0.000407

AC XY:

AN XY:

56550

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000211

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000493

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000551

Gnomad OTH exome

AF:

0.000383

GnomAD4 exome

AF:

0.000427

AC:

574

AN:

1345128

Hom.:

Cov.:

AF XY:

0.000454

AC XY:

302

AN XY:

664542

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000163

Gnomad4 ASJ exome

AF:

0.0000842

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000293

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000482

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000381

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.0000530

Hom.:

Bravo

AF:

0.000378

ExAC

AF:

0.000280

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

Feb 05, 2024

The c.155C>T (p.A52V) alteration is located in exon 1 (coding exon 1) of the LKAAEAR1 gene. This alteration results from a C to T substitution at nucleotide position 155, causing the alanine (A) at amino acid position 52 to be replaced by a valine (V). 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

0.12

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.032

.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.48

T;T

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.015

Sift

Benign

0.33

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.045

B;.

Vest4

0.072

MVP

0.014

MPC

1.1

ClinPred

0.019

GERP RS

-5.8

Varity_R

0.029

gMVP

0.058

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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