rs17484286

Positions:

• chr12-40304884-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198578.4(LRRK2):​c.3777+750A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0814 in 152,130 control chromosomes in the GnomAD database, including 701 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.081 (701 hom., cov: 32)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.150

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.3777+750A>G		intron_variant		ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.3777+750A>G		intron_variant		1	NM_198578.4	ENSP00000298910	P1

Frequencies

GnomAD3 genomes AF: 0.0814 AC: 12378 AN: 152000 Hom.: 700 Cov.: 32

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0901

Gnomad ASJ AF: 0.0958

Gnomad EAS AF: 0.314

Gnomad SAS AF: 0.0954

Gnomad FIN AF: 0.0838

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0975

Gnomad OTH AF: 0.0805

GnomAD4 exome AF: 0.167 AC: 2 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.100 AC XY: 1 AN XY: 10

Gnomad4 NFE exome AF: 0.167

GnomAD4 genome AF: 0.0814 AC: 12383 AN: 152118 Hom.: 701 Cov.: 32 AF XY: 0.0818 AC XY: 6081 AN XY: 74374

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.0903

Gnomad4 ASJ AF: 0.0958

Gnomad4 EAS AF: 0.314

Gnomad4 SAS AF: 0.0959

Gnomad4 FIN AF: 0.0838

Gnomad4 NFE AF: 0.0975

Gnomad4 OTH AF: 0.0801

Alfa AF: 0.0914 Hom.: 275

Bravo AF: 0.0822

Asia WGS AF: 0.201 AC: 698 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.8
DANN	Benign	0.37

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: rs17484286; hg19: chr12-40698686;