rs281865054

chr12-40323270-G-Achr12-40323270-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198578.4(LRRK2):c.5620G>A(p.Glu1874Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,790 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E1874E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.23

Genes affected

LRRK2 (HGNC:18618): (leucine rich repeat kinase 2) This gene is a member of the leucine-rich repeat kinase family and encodes a protein with an ankryin repeat region, a leucine-rich repeat (LRR) domain, a kinase domain, a DFG-like motif, a RAS domain, a GTPase domain, a MLK-like domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Mutations in this gene have been associated with Parkinson disease-8. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19257078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.5620G>A	p.Glu1874Lys	missense_variant	38/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.5620G>A	p.Glu1874Lys	missense_variant	38/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251202 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460790 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726642

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.0036
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.13
Sift	Benign	0.29	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.0060	B
Vest4		0.26
MutPred		0.50		Gain of ubiquitination at E1874 (P = 0.0162);
MVP		0.91
MPC		0.098
ClinPred		0.67	D
GERP RS		5.3
Varity_R		0.35
gMVP		0.59

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: rs281865054; hg19: chr12-40717072;