rs11175964

Variant names:

• chr12-40309185-G-A
• rs11175964
• NM_198578.4:c.4269G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-40309185-G-A
• chr12-40309185-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198578.4(LRRK2):​c.4269G>A​(p.Lys1423Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,613,646 control chromosomes in the GnomAD database, including 4,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (391 hom., cov: 32)
  • Exomes 𝑓: 0.069 (3898 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.22
• Publications: 51 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

ENSG00000258167 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 12-40309185-G-A is Benign according to our data. Variant chr12-40309185-G-A is described in ClinVar as Benign. ClinVar VariationId is 39181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.123 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.4269G>A	p.Lys1423Lys	synonymous	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.4269G>A	p.Lys1423Lys	synonymous	Exon 30 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000430804.5	TSL:1	n.*942G>A		non_coding_transcript_exon	Exon 9 of 30	ENSP00000410821.1	H7C3B6
	LRRK2	ENST00000430804.5	TSL:1	n.*942G>A		3_prime_UTR	Exon 9 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes AF: 0.0603 AC: 9160 AN: 151992 Hom.: 391 Cov.: 32

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.0413

Gnomad FIN AF: 0.0546

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0686

Gnomad OTH AF: 0.0738

GnomAD2 exomes AF: 0.0746 AC: 18742 AN: 251084 AF XY: 0.0718

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.0878

Gnomad EAS exome AF: 0.0985

Gnomad FIN exome AF: 0.0553

Gnomad NFE exome AF: 0.0721

Gnomad OTH exome AF: 0.0690

GnomAD4 exome AF: 0.0688 AC: 100604 AN: 1461536 Hom.: 3898 Cov.: 34 AF XY: 0.0678 AC XY: 49327 AN XY: 727060

African (AFR) AF: 0.0158 AC: 529 AN: 33472

American (AMR) AF: 0.137 AC: 6120 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0882 AC: 2303 AN: 26118

East Asian (EAS) AF: 0.120 AC: 4763 AN: 39666

South Asian (SAS) AF: 0.0392 AC: 3380 AN: 86246

European-Finnish (FIN) AF: 0.0564 AC: 3014 AN: 53404

Middle Eastern (MID) AF: 0.0439 AC: 253 AN: 5764

European-Non Finnish (NFE) AF: 0.0684 AC: 76073 AN: 1111800

Other (OTH) AF: 0.0691 AC: 4169 AN: 60366

GnomAD4 genome AF: 0.0602 AC: 9158 AN: 152110 Hom.: 391 Cov.: 32 AF XY: 0.0612 AC XY: 4552 AN XY: 74362

African (AFR) AF: 0.0180 AC: 749 AN: 41520

American (AMR) AF: 0.128 AC: 1952 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0916 AC: 318 AN: 3470

East Asian (EAS) AF: 0.0995 AC: 515 AN: 5176

South Asian (SAS) AF: 0.0411 AC: 198 AN: 4820

European-Finnish (FIN) AF: 0.0546 AC: 578 AN: 10578

Middle Eastern (MID) AF: 0.0719 AC: 21 AN: 292

European-Non Finnish (NFE) AF: 0.0686 AC: 4663 AN: 67974

Other (OTH) AF: 0.0720 AC: 152 AN: 2110

Alfa AF: 0.0658 Hom.: 832

Bravo AF: 0.0645

Asia WGS AF: 0.0600 AC: 209 AN: 3478

EpiCase AF: 0.0701

EpiControl AF: 0.0670

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.1
DANN	Benign	0.56
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs11175964; hg19: chr12-40702987; COSMIC: COSV54176653; COSMIC: COSV54176653;