rs11564148

Positions:

• chr12-40320099-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198578.4(LRRK2):​c.4939T>A​(p.Ser1647Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,609,436 control chromosomes in the GnomAD database, including 74,287 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1647S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (5907 hom., cov: 32)
  • Exomes 𝑓: 0.30 (68380 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.829

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012919903).
• BP6: Variant 12-40320099-T-A is Benign according to our data. Variant chr12-40320099-T-A is described in ClinVar as [Benign]. Clinvar id is 39201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40320099-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.4939T>A	p.Ser1647Thr	missense_variant	34/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.4939T>A	p.Ser1647Thr	missense_variant	34/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41281 AN: 151744 Hom.: 5906 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.259

GnomAD3 exomes AF: 0.298 AC: 74234 AN: 249470 Hom.: 11750 AF XY: 0.304 AC XY: 41010 AN XY: 135114

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.339

Gnomad SAS exome AF: 0.369

Gnomad FIN exome AF: 0.371

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.297

GnomAD4 exome AF: 0.302 AC: 440219 AN: 1457574 Hom.: 68380 Cov.: 34 AF XY: 0.304 AC XY: 220692 AN XY: 725254

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.212

Gnomad4 ASJ exome AF: 0.274

Gnomad4 EAS exome AF: 0.321

Gnomad4 SAS exome AF: 0.365

Gnomad4 FIN exome AF: 0.368

Gnomad4 NFE exome AF: 0.302

Gnomad4 OTH exome AF: 0.299

GnomAD4 genome AF: 0.272 AC: 41295 AN: 151862 Hom.: 5907 Cov.: 32 AF XY: 0.276 AC XY: 20450 AN XY: 74226

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.246

Gnomad4 ASJ AF: 0.274

Gnomad4 EAS AF: 0.340

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.361

Gnomad4 NFE AF: 0.308

Gnomad4 OTH AF: 0.260

Alfa AF: 0.300 Hom.: 5361

Bravo AF: 0.256

TwinsUK AF: 0.302 AC: 1119

ALSPAC AF: 0.304 AC: 1172

ESP6500AA AF: 0.179 AC: 787

ESP6500EA AF: 0.298 AC: 2561

ExAC AF: 0.296 AC: 35962

Asia WGS AF: 0.340 AC: 1177 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2021

This variant is associated with the following publications: (PMID: 30917570, 23842774, 20629711, 20721913, 31085292, 20186690, 26311745) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.5
DANN	Benign	0.69
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.39	N
MutationTaster	Benign	0.096	P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.086
Sift	Benign	0.95	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.037
MPC		0.078
ClinPred		0.00020	T
GERP RS		0.45
Varity_R		0.093
gMVP		0.15

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: rs11564148; hg19: chr12-40713901; COSMIC: COSV54145756; COSMIC: COSV54145756;