rs7133914

Variant names:

• chr12-40309109-G-A
• rs7133914
• NM_198578.4:c.4193G>A
• LRRK2 p.Arg1398His

Your query was ambiguous. Multiple possible variants found:

• chr12-40309109-G-A
• chr12-40309109-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198578.4(LRRK2):​c.4193G>A​(p.Arg1398His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,612,476 control chromosomes in the GnomAD database, including 5,310 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1398L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.097 (905 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4405 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 3.13
• Publications: 149 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

ENSG00000258167 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027324557).
• BP6: Variant 12-40309109-G-A is Benign according to our data. Variant chr12-40309109-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 39178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

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.4193G>A	p.Arg1398His	missense	Exon 30 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.4193G>A	p.Arg1398His	missense	Exon 30 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000430804.5	TSL:1	n.*866G>A		non_coding_transcript_exon	Exon 9 of 30	ENSP00000410821.1	H7C3B6
	LRRK2	ENST00000430804.5	TSL:1	n.*866G>A		3_prime_UTR	Exon 9 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes AF: 0.0973 AC: 14774 AN: 151798 Hom.: 905 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.0417

Gnomad FIN AF: 0.0551

Gnomad MID AF: 0.0892

Gnomad NFE AF: 0.0694

Gnomad OTH AF: 0.101

GnomAD2 exomes AF: 0.0848 AC: 21271 AN: 250816 AF XY: 0.0793

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.0933

Gnomad EAS exome AF: 0.0985

Gnomad FIN exome AF: 0.0554

Gnomad NFE exome AF: 0.0727

Gnomad OTH exome AF: 0.0765

GnomAD4 exome AF: 0.0728 AC: 106332 AN: 1460560 Hom.: 4405 Cov.: 34 AF XY: 0.0713 AC XY: 51824 AN XY: 726604

African (AFR) AF: 0.142 AC: 4758 AN: 33426

American (AMR) AF: 0.148 AC: 6590 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0935 AC: 2441 AN: 26104

East Asian (EAS) AF: 0.120 AC: 4764 AN: 39662

South Asian (SAS) AF: 0.0394 AC: 3399 AN: 86212

European-Finnish (FIN) AF: 0.0566 AC: 3020 AN: 53402

Middle Eastern (MID) AF: 0.0506 AC: 290 AN: 5730

European-Non Finnish (NFE) AF: 0.0687 AC: 76346 AN: 1111030

Other (OTH) AF: 0.0783 AC: 4724 AN: 60334

GnomAD4 genome AF: 0.0973 AC: 14780 AN: 151916 Hom.: 905 Cov.: 32 AF XY: 0.0970 AC XY: 7202 AN XY: 74242

African (AFR) AF: 0.142 AC: 5861 AN: 41410

American (AMR) AF: 0.152 AC: 2317 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 347 AN: 3468

East Asian (EAS) AF: 0.0997 AC: 516 AN: 5174

South Asian (SAS) AF: 0.0415 AC: 200 AN: 4816

European-Finnish (FIN) AF: 0.0551 AC: 580 AN: 10522

Middle Eastern (MID) AF: 0.0890 AC: 26 AN: 292

European-Non Finnish (NFE) AF: 0.0693 AC: 4713 AN: 67972

Other (OTH) AF: 0.0988 AC: 208 AN: 2106

Alfa AF: 0.0786 Hom.: 2177

Bravo AF: 0.108

Asia WGS AF: 0.0680 AC: 239 AN: 3478

EpiCase AF: 0.0718

EpiControl AF: 0.0682

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal dominant Parkinson disease 8 (4)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.070
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.77	N
PhyloP100		3.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.37
Sift	Benign	0.10	T
Sift4G	Benign	0.14	T
Varity_R		0.19
gMVP		0.42
Mutation Taster		=80/20	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs7133914;

hg19: chr12-40702911;

COSMIC: COSV54150715;

COSMIC: COSV54150715;