rs33995463

Variant names:

• chr12-40235634-T-C
• rs33995463
• NM_198578.4:c.356T>C

Variant summary

Our verdict is Benign. The variant received -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:4 O:1
• Conservation: PhyloP100: 5.35
• Publications: 24 publications found

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]

LRRK2 Gene-Disease associations (from GenCC):

• autosomal dominant Parkinson disease 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 39167.
• BS2: High AC in GnomAd4 at 209 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198578.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.356T>C	p.Leu119Pro	missense	Exon 4 of 51	NP_940980.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.356T>C	p.Leu119Pro	missense	Exon 4 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000950031.1		c.356T>C	p.Leu119Pro	missense	Exon 4 of 51	ENSP00000620090.1
	LRRK2	ENST00000680790.1		c.356T>C	p.Leu119Pro	missense	Exon 4 of 49	ENSP00000505335.1	A0A7P0T8S1

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

GnomAD2 exomes AF: 0.00125 AC: 313 AN: 251148 AF XY: 0.00136

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 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

African (AFR) AF: 0.000301 AC: 10 AN: 33244

American (AMR) AF: 0.00152 AC: 68 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86038

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53294

Middle Eastern (MID) AF: 0.000872 AC: 5 AN: 5732

European-Non Finnish (NFE) AF: 0.00228 AC: 2514 AN: 1101380

Other (OTH) AF: 0.00175 AC: 105 AN: 60028

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

African (AFR) AF: 0.000601 AC: 25 AN: 41590

American (AMR) AF: 0.00150 AC: 23 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00229 AC: 156 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00206 Hom.: 1

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Autosomal dominant Parkinson disease 8 (3)
-	1	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.88
MPC		0.55
ClinPred		0.040	T
GERP RS		5.8
Varity_R		0.84
gMVP		0.79
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs33995463; hg19: chr12-40629436;