20-64084105-G-C

Variant names:

• chr20-64084105-G-C
• rs971916257
• NM_001353425.2:c.115C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001353425.2(LKAAEAR1):​c.115C>G​(p.Pro39Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P39S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LKAAEAR1 NM_001353425.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.267
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059499502).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353425.2. 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
	LKAAEAR1	NM_001353425.2	MANE Select	c.115C>G	p.Pro39Ala	missense	Exon 1 of 3	NP_001340354.1	Q8TD35-1
	OPRL1	NM_182647.4	MANE Select	c.-185+3753G>C		intron	N/A	NP_872588.1	P41146-1
	LKAAEAR1	NM_001007125.3		c.115C>G	p.Pro39Ala	missense	Exon 1 of 2	NP_001007126.1	Q8TD35-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LKAAEAR1	ENST00000302096.5	TSL:2 MANE Select	c.115C>G	p.Pro39Ala	missense	Exon 1 of 3	ENSP00000302763.4	Q8TD35-1
	LKAAEAR1	ENST00000308906.6	TSL:1	c.115C>G	p.Pro39Ala	missense	Exon 1 of 2	ENSP00000310801.2	Q8TD35-2
	OPRL1	ENST00000336866.7	TSL:5 MANE Select	c.-185+3753G>C		intron	N/A	ENSP00000336843.2	P41146-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1322800 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 651536

African (AFR) AF: 0.00 AC: 0 AN: 26806

American (AMR) AF: 0.00 AC: 0 AN: 26726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23312

East Asian (EAS) AF: 0.00 AC: 0 AN: 28324

South Asian (SAS) AF: 0.00 AC: 0 AN: 72806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3958

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1053084

Other (OTH) AF: 0.00 AC: 0 AN: 54888

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.27
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.029
Sift	Benign	0.20	T
Sift4G	Benign	0.64	T
Polyphen		0.15	B
Vest4		0.11
MutPred		0.22		Loss of catalytic residue at P39 (P = 5e-04)
MVP		0.14
MPC		1.0
ClinPred		0.14	T
GERP RS		1.4
PromoterAI		0.16	Neutral
Varity_R		0.034
gMVP		0.089
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs971916257; hg19: chr20-62715458;