20-64083697-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001353425.2(LKAAEAR1):c.411G>C(p.Glu137Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000242 in 1,241,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: LKAAEAR1 NM_001353425.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.371

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2721583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LKAAEAR1	NM_001353425.2	c.411G>C	p.Glu137Asp	missense_variant	2/3	ENST00000302096.5
OPRL1	NM_182647.4	c.-185+3345C>G		intron_variant		ENST00000336866.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LKAAEAR1	ENST00000302096.5	c.411G>C	p.Glu137Asp	missense_variant	2/3	2	NM_001353425.2	P1
OPRL1	ENST00000336866.7	c.-185+3345C>G		intron_variant		5	NM_182647.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000242 AC: 3 AN: 1241594 Hom.: 0 Cov.: 38 AF XY: 0.00000166 AC XY: 1 AN XY: 602766

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: 0.00000296

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jun 23, 2023

The c.411G>C (p.E137D) alteration is located in exon 2 (coding exon 2) of the LKAAEAR1 gene. This alteration results from a G to C substitution at nucleotide position 411, causing the glutamic acid (E) at amino acid position 137 to be replaced by an aspartic acid (D). 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	Pathogenic	0.76
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.51	T;T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	N;N;D;D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.060	T;D
Polyphen		1.0	D;.
Vest4		0.40
MutPred		0.22		Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.20
MPC		1.7
ClinPred		0.97	D
GERP RS		-0.78
Varity_R		0.53
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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: chr20-62715050;