rs34410987

chr12-40283897-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_198578.4(LRRK2):c.2264C>T(p.Pro755Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000245 in 1,612,866 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P755T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 4.50

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074314773).
• BP6: Variant 12-40283897-C-T is Benign according to our data. Variant chr12-40283897-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 39148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40283897-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.2264C>T	p.Pro755Leu	missense_variant	19/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.2264C>T	p.Pro755Leu	missense_variant	19/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.000290 AC: 44 AN: 151884 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000741 AC: 186 AN: 250934 Hom.: 0 AF XY: 0.000671 AC XY: 91 AN XY: 135596

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00954

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000240 AC: 351 AN: 1460866 Hom.: 1 Cov.: 31 AF XY: 0.000211 AC XY: 153 AN XY: 726690

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00633

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74282

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00560

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000364 Hom.: 1

Bravo AF: 0.000495

ExAC AF: 0.000692 AC: 84

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:4 Other:1

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The LRRK2 p.P755L variant was identified in several heterozygous individuals with Parkinson's disease; however, this variant was also identified in several unaffected controls (Yuan_2016_PMID: 27653456; Tomioyama_2008_PMID: 18923807; Di Fonzo_2006_PMID: 16633828; Tan_2008_PMID: 18265005). The variant was identified in dbSNP (ID: rs34410987) and ClinVar (classified as benign by Invitae and as likely benign by Illumina). The variant was identified in control databases in 198 of 282288 chromosomes at a frequency of 0.0007014, and was observed at the highest frequency in the East Asian population in 185 of 19908 chromosomes (freq: 0.009293) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.P755 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. Functional studies show that this variant has similar expression levels and activity compared to wild-type (Fava_2019_PMID: 31308240). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 11, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

This variant is associated with the following publications: (PMID: 30598256, 25558820, 30049590, 17179858, 22575234, 24488318, 22988870, 20642453) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	-0.042
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0074	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.2	N;D;N
REVEL	Benign	0.17
Sift	Benign	0.35	T;T;T
Sift4G	Uncertain	0.0090	D;D;T
Polyphen		0.65, 0.13	.;P;B
Vest4		0.35, 0.29
MVP		0.80
MPC		0.41
ClinPred		0.060	T
GERP RS		5.3
Varity_R		0.15
gMVP		0.18

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: rs34410987; hg19: chr12-40677699; COSMIC: COSV100111106; COSMIC: COSV100111106;