rs72546338

chr12-40308481-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5 BS2

The NM_198578.4(LRRK2):c.3974G>A(p.Arg1325Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000366 in 1,613,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1325R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 O:1
• Conservation: PhyloP100: 9.29

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 Likely_benign. Variant got -3 ACMG points.

• PP5: Variant 12-40308481-G-A is Pathogenic according to our data. Variant chr12-40308481-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39175.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Likely_pathogenic=1}.
• BS2: High AC in GnomAd at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.3974G>A	p.Arg1325Gln	missense_variant	29/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.3974G>A	p.Arg1325Gln	missense_variant	29/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000188 AC: 47 AN: 249858 Hom.: 0 AF XY: 0.000222 AC XY: 30 AN XY: 135336

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000383 AC: 560 AN: 1461020 Hom.: 0 Cov.: 31 AF XY: 0.000382 AC XY: 278 AN XY: 726824

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000459

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74290

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000275 Hom.: 0

Bravo AF: 0.000151

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Pathogenic:1 Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1325 of the LRRK2 protein (p.Arg1325Gln). This variant is present in population databases (rs72546338, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Parkinson disease (PMID: 18197194, 19405094, 21885347, 30598256). ClinVar contains an entry for this variant (Variation ID: 39175). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Apr 21, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 05, 2022

Reported previously in individuals with Parkinson disease; however, the R1325Q variant was also observed in healthy control individuals in published literature (Zhang et al., 2018; Foo et al., 2014; Lesage et al., 2009); Reported as heterozygous in an individual with Parkinson disease and as homozygous in the individual's mother with tremor in published literature (Nuytemans et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19405094, 19472409, 31161537, 21885347, 18197194, 34426522, 20301387, 18973807, 30598256, 33272183, 33454605, 30049590, 24565865, 19357115, Kalogeropulou2022[functionalstudy]) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.55
Sift	Benign	0.094	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MVP		0.94
MPC		0.50
ClinPred		0.28	T
GERP RS		5.6
Varity_R		0.28
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72546338; hg19: chr12-40702283; COSMIC: COSV100108804; COSMIC: COSV100108804;