rs33995463

chr12-40235634-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_198578.4(LRRK2):c.356T>C(p.Leu119Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00182 in 1,602,432 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L119F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (4 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:1
• Conservation: PhyloP100: 5.35

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026334167).
• BP6: Variant 12-40235634-T-C is Benign according to our data. Variant chr12-40235634-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39167.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, not_provided=1, Uncertain_significance=1}. Variant chr12-40235634-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 209 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.356T>C	p.Leu119Pro	missense_variant	4/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.356T>C	p.Leu119Pro	missense_variant	4/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00125 AC: 313 AN: 251148 Hom.: 0 AF XY: 0.00136 AC XY: 185 AN XY: 135772

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00225

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00187 AC: 2713 AN: 1450072 Hom.: 4 Cov.: 29 AF XY: 0.00184 AC XY: 1329 AN XY: 722338

Gnomad4 AFR exome AF: 0.000301

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.00228

Gnomad4 OTH exome AF: 0.00175

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74504

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00224 Hom.: 0

Bravo AF: 0.00135

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00128 AC: 156

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2022	Reported previously in individuals with Parkinson disease, however L119P was also seen in control subjects (Jasinska-Myga et al., 2010; Ross et al., 2011; Benitez et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28130640, 25466404, 31980526, 33836114, 31996268, 29369408, 27393345, 32557143, 28842327, 20721913, 25174650, 27294386, 21885347, 27094865, 34542912, Kalogeropulou2022[functionalstudy], 33454605) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	LRRK2: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.026	T;T;T
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.92, 0.93
MVP		0.88
MPC		0.55
ClinPred		0.040	T
GERP RS		5.8
Varity_R		0.84
gMVP		0.79

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: rs33995463; hg19: chr12-40629436;