20-64084065-G-A

Position:

• chr20-64084065-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.283

Genes affected

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

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]

ACMG classification

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	UniProt
LKAAEAR1	NM_001353425.2	c.155C>T	p.Ala52Val	missense_variant	1/3	ENST00000302096.5
OPRL1	NM_182647.4	c.-185+3713G>A		intron_variant		ENST00000336866.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LKAAEAR1	ENST00000302096.5	c.155C>T	p.Ala52Val	missense_variant	1/3	2	NM_001353425.2	P1
OPRL1	ENST00000336866.7	c.-185+3713G>A		intron_variant		5	NM_182647.4	P1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152040 Hom.: 0 Cov.: 33

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: 36 AN: 98202 Hom.: 0 AF XY: 0.000407 AC XY: 23 AN XY: 56550

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.: 0 Cov.: 35 AF XY: 0.000454 AC XY: 302 AN XY: 664542

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: 58 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74412

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.: 0

Bravo AF: 0.000378

ExAC AF: 0.000280 AC: 29

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

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	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.032	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.0082	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N;N;N
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	T
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

Other links and lift over

dbSNP: rs555074600; hg19: chr20-62715418;