chr12-40363528-A-G

Variant names:

• chr12-40363528-A-G
• rs33962975
• NM_198578.4:c.7155A>G

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.7155A>G​(p.Gly2385Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,611,208 control chromosomes in the GnomAD database, including 16,076 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1252 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14824 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.34
• Publications: 29 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=-0.52).
• BP6: Variant 12-40363528-A-G is Benign according to our data. Variant chr12-40363528-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 39234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.144 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.7155A>G	p.Gly2385Gly	synonymous	Exon 48 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.7155A>G	p.Gly2385Gly	synonymous	Exon 48 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000430804.5	TSL:1	n.*3828A>G		non_coding_transcript_exon	Exon 27 of 30	ENSP00000410821.1	H7C3B6
	LRRK2	ENST00000430804.5	TSL:1	n.*3828A>G		3_prime_UTR	Exon 27 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16574 AN: 151864 Hom.: 1250 Cov.: 32

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.0841

Gnomad ASJ AF: 0.0808

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.102

GnomAD2 exomes AF: 0.113 AC: 28221 AN: 250616 AF XY: 0.112

Gnomad AFR exome AF: 0.0376

Gnomad AMR exome AF: 0.0745

Gnomad ASJ exome AF: 0.0810

Gnomad EAS exome AF: 0.0170

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.134 AC: 195465 AN: 1459226 Hom.: 14824 Cov.: 34 AF XY: 0.132 AC XY: 95495 AN XY: 725966

African (AFR) AF: 0.0384 AC: 1281 AN: 33364

American (AMR) AF: 0.0742 AC: 3304 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.0811 AC: 2110 AN: 26024

East Asian (EAS) AF: 0.0164 AC: 648 AN: 39570

South Asian (SAS) AF: 0.0364 AC: 3142 AN: 86220

European-Finnish (FIN) AF: 0.243 AC: 12947 AN: 53344

Middle Eastern (MID) AF: 0.0909 AC: 523 AN: 5752

European-Non Finnish (NFE) AF: 0.148 AC: 163972 AN: 1110182

Other (OTH) AF: 0.125 AC: 7538 AN: 60226

GnomAD4 genome AF: 0.109 AC: 16586 AN: 151982 Hom.: 1252 Cov.: 32 AF XY: 0.111 AC XY: 8278 AN XY: 74296

African (AFR) AF: 0.0411 AC: 1704 AN: 41492

American (AMR) AF: 0.0839 AC: 1279 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0808 AC: 280 AN: 3464

East Asian (EAS) AF: 0.0165 AC: 85 AN: 5162

South Asian (SAS) AF: 0.0269 AC: 130 AN: 4824

European-Finnish (FIN) AF: 0.256 AC: 2703 AN: 10574

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9965 AN: 67910

Other (OTH) AF: 0.101 AC: 212 AN: 2104

Alfa AF: 0.117 Hom.: 996

Bravo AF: 0.0949

Asia WGS AF: 0.0380 AC: 131 AN: 3478

EpiCase AF: 0.140

EpiControl AF: 0.139

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)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.0
DANN	Benign	0.62
PhyloP100		1.3
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: rs33962975; hg19: chr12-40757330;