chr20-64084105-G-A

Variant names:

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

Variant summary

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

The NM_001353425.2(LKAAEAR1):​c.115C>T​(p.Pro39Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000542 in 1,474,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000053 (0 hom.)
• Consequence: LKAAEAR1 NM_001353425.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: 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=0.071224004).

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>T	p.Pro39Ser	missense	Exon 1 of 3	NP_001340354.1	Q8TD35-1
	OPRL1	NM_182647.4	MANE Select	c.-185+3753G>A		intron	N/A	NP_872588.1	P41146-1
	LKAAEAR1	NM_001007125.3		c.115C>T	p.Pro39Ser	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>T	p.Pro39Ser	missense	Exon 1 of 3	ENSP00000302763.4	Q8TD35-1
	LKAAEAR1	ENST00000308906.6	TSL:1	c.115C>T	p.Pro39Ser	missense	Exon 1 of 2	ENSP00000310801.2	Q8TD35-2
	OPRL1	ENST00000336866.7	TSL:5 MANE Select	c.-185+3753G>A		intron	N/A	ENSP00000336843.2	P41146-1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152032 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000529 AC: 7 AN: 1322800 Hom.: 0 Cov.: 35 AF XY: 0.00000307 AC XY: 2 AN XY: 651536

African (AFR) AF: 0.000224 AC: 6 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: 0.0000137 AC: 1 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 AF: 0.00000658 AC: 1 AN: 152032 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74286

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67944

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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	0.091
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.27
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.041
Sift	Benign	0.29	T
Sift4G	Benign	0.52	T
Polyphen		0.55	P
Vest4		0.070
MutPred		0.22		Loss of catalytic residue at P39 (P = 2e-04)
MVP		0.20
MPC		1.3
ClinPred		0.46	T
GERP RS		1.4
PromoterAI		0.12	Neutral
Varity_R		0.027
gMVP		0.19
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;