rs78501232

Variant names:

• chr12-40251273-G-A
• rs78501232
• NM_198578.4:c.1000G>A

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.1000G>A​(p.Glu334Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,609,600 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. E334D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (18 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: 2.58
• Publications: 17 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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=0.0052466393).
• BP6: Variant 12-40251273-G-A is Benign according to our data. Variant chr12-40251273-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 39128.
• BS2: High AC in GnomAd4 at 380 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.1000G>A	p.Glu334Lys	missense	Exon 9 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.1000G>A	p.Glu334Lys	missense	Exon 9 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000950031.1		c.976G>A	p.Glu326Lys	missense	Exon 9 of 51	ENSP00000620090.1
	LRRK2	ENST00000680790.1		c.1000G>A	p.Glu334Lys	missense	Exon 9 of 49	ENSP00000505335.1	A0A7P0T8S1

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 151878 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.00283 AC: 703 AN: 248512 AF XY: 0.00271

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0253

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00142 AC: 2073 AN: 1457604 Hom.: 18 Cov.: 30 AF XY: 0.00144 AC XY: 1042 AN XY: 725058

African (AFR) AF: 0.0000299 AC: 1 AN: 33394

American (AMR) AF: 0.0000225 AC: 1 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85624

European-Finnish (FIN) AF: 0.0233 AC: 1244 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000666 AC: 739 AN: 1109104

Other (OTH) AF: 0.00130 AC: 78 AN: 60210

GnomAD4 genome AF: 0.00250 AC: 380 AN: 151996 Hom.: 1 Cov.: 32 AF XY: 0.00335 AC XY: 249 AN XY: 74314

African (AFR) AF: 0.0000241 AC: 1 AN: 41494

American (AMR) AF: 0.000197 AC: 3 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.0252 AC: 266 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 67968

Other (OTH) AF: 0.000951 AC: 2 AN: 2102

Alfa AF: 0.000981 Hom.: 1

Bravo AF: 0.000442

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00232 AC: 282

EpiCase AF: 0.000827

EpiControl AF: 0.000602

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Autosomal dominant Parkinson disease 8 (4)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.074
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.19
Sift	Benign	0.16	T
Sift4G	Benign	0.082	T
Polyphen		0.028	B
Vest4		0.72
MVP		0.91
MPC		0.098
ClinPred		0.030	T
GERP RS		4.1
Varity_R		0.15
gMVP		0.23
Mutation Taster		=79/21	polymorphism

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: rs78501232; hg19: chr12-40645075; COSMIC: COSV105883128;