chr12-40348452-G-A

Variant names:

• chr12-40348452-G-A
• rs10878405
• NM_198578.4:c.6324G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_198578.4(LRRK2):​c.6324G>A​(p.Glu2108Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,607,610 control chromosomes in the GnomAD database, including 80,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6173 hom., cov: 33)
  • Exomes 𝑓: 0.31 (73852 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 3.27
• Publications: 32 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 12-40348452-G-A is Benign according to our data. Variant chr12-40348452-G-A is described in ClinVar as Benign. ClinVar VariationId is 39222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.354 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.6324G>A	p.Glu2108Glu	synonymous	Exon 43 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.6324G>A	p.Glu2108Glu	synonymous	Exon 43 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000430804.5	TSL:1	n.*2997G>A		non_coding_transcript_exon	Exon 22 of 30	ENSP00000410821.1	H7C3B6
	LRRK2	ENST00000430804.5	TSL:1	n.*2997G>A		3_prime_UTR	Exon 22 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41286 AN: 151872 Hom.: 6171 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.264

GnomAD2 exomes AF: 0.302 AC: 75665 AN: 250916 AF XY: 0.309

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.272

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.317

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.313 AC: 456015 AN: 1455620 Hom.: 73852 Cov.: 32 AF XY: 0.315 AC XY: 228474 AN XY: 724384

African (AFR) AF: 0.142 AC: 4731 AN: 33398

American (AMR) AF: 0.214 AC: 9577 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 7145 AN: 26084

East Asian (EAS) AF: 0.320 AC: 12635 AN: 39538

South Asian (SAS) AF: 0.360 AC: 30953 AN: 86062

European-Finnish (FIN) AF: 0.381 AC: 20324 AN: 53378

Middle Eastern (MID) AF: 0.238 AC: 1334 AN: 5600

European-Non Finnish (NFE) AF: 0.317 AC: 350975 AN: 1106696

Other (OTH) AF: 0.305 AC: 18341 AN: 60176

GnomAD4 genome AF: 0.272 AC: 41305 AN: 151990 Hom.: 6173 Cov.: 33 AF XY: 0.278 AC XY: 20613 AN XY: 74274

African (AFR) AF: 0.148 AC: 6120 AN: 41462

American (AMR) AF: 0.259 AC: 3959 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 916 AN: 3472

East Asian (EAS) AF: 0.341 AC: 1766 AN: 5180

South Asian (SAS) AF: 0.368 AC: 1778 AN: 4826

European-Finnish (FIN) AF: 0.377 AC: 3962 AN: 10502

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 22001 AN: 67968

Other (OTH) AF: 0.266 AC: 562 AN: 2116

Alfa AF: 0.293 Hom.: 12129

Bravo AF: 0.253

Asia WGS AF: 0.337 AC: 1167 AN: 3472

EpiCase AF: 0.305

EpiControl AF: 0.310

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal dominant Parkinson disease 8 (4)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	6.6
DANN	Benign	0.56
PhyloP100		3.3
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: rs10878405; hg19: chr12-40742254; COSMIC: COSV54147530;