ENST00000308906.6:c.542G>C

Variant names:

• chr20-64083566-C-G
• rs574948146
• ENST00000308906.6:c.542G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000308906.6(LKAAEAR1):​c.542G>C​(p.Gly181Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,375,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G181D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: LKAAEAR1 ENST00000308906.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0410
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06922582).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000308906.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPRL1	NM_182647.4	MANE Select	c.-185+3214C>G		intron	N/A	NP_872588.1	P41146-1
	LKAAEAR1	NM_001353425.2	MANE Select	c.525+17G>C		intron	N/A	NP_001340354.1	Q8TD35-1
	LKAAEAR1	NM_001007125.3		c.542G>C	p.Gly181Ala	missense	Exon 2 of 2	NP_001007126.1	Q8TD35-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LKAAEAR1	ENST00000308906.6	TSL:1	c.542G>C	p.Gly181Ala	missense	Exon 2 of 2	ENSP00000310801.2	Q8TD35-2
	OPRL1	ENST00000336866.7	TSL:5 MANE Select	c.-185+3214C>G		intron	N/A	ENSP00000336843.2	P41146-1
	LKAAEAR1	ENST00000302096.5	TSL:2 MANE Select	c.525+17G>C		intron	N/A	ENSP00000302763.4	Q8TD35-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1375378 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 677518

African (AFR) AF: 0.00 AC: 0 AN: 30566

American (AMR) AF: 0.00 AC: 0 AN: 32166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23458

East Asian (EAS) AF: 0.00 AC: 0 AN: 35238

South Asian (SAS) AF: 0.0000257 AC: 2 AN: 77968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5556

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069246

Other (OTH) AF: 0.00 AC: 0 AN: 56822

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.69
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.041
PROVEAN	Benign	1.4	N
REVEL	Benign	0.083
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.18	T
Polyphen		0.70	P
Vest4		0.13
MutPred		0.095		Loss of methylation at R182 (P = 0.1013)
MVP		0.055
MPC		1.0
ClinPred		0.37	T
GERP RS		0.89
gMVP		0.017
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs574948146; hg19: chr20-62714919;