chr12-40309350-C-A

Variant names:

• chr12-40309350-C-A
• rs11175966
• NM_198578.4:c.4317+117C>A

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.4317+117C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,311,974 control chromosomes in the GnomAD database, including 27,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2246 hom., cov: 32)
  • Exomes 𝑓: 0.20 (24977 hom.)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.61
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• 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 (BayesDel_noAF=-0.84).
• BP6: Variant 12-40309350-C-A is Benign according to our data. Variant chr12-40309350-C-A is described in ClinVar as Benign. ClinVar VariationId is 1279653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.4317+117C>A		intron	N/A	NP_940980.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.4317+117C>A		intron	N/A	ENSP00000298910.7
	LRRK2	ENST00000430804.5	TSL:1	n.*990+117C>A		intron	N/A	ENSP00000410821.1
	LRRK2	ENST00000680790.1		c.4062+117C>A		intron	N/A	ENSP00000505335.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23496 AN: 151726 Hom.: 2247 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.191

GnomAD4 exome AF: 0.203 AC: 235354 AN: 1160130 Hom.: 24977 AF XY: 0.202 AC XY: 116023 AN XY: 574466

African (AFR) AF: 0.0441 AC: 1124 AN: 25478

American (AMR) AF: 0.148 AC: 3099 AN: 20974

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 5494 AN: 20068

East Asian (EAS) AF: 0.197 AC: 6617 AN: 33648

South Asian (SAS) AF: 0.156 AC: 9876 AN: 63146

European-Finnish (FIN) AF: 0.127 AC: 4449 AN: 35000

Middle Eastern (MID) AF: 0.254 AC: 882 AN: 3478

European-Non Finnish (NFE) AF: 0.214 AC: 194208 AN: 909336

Other (OTH) AF: 0.196 AC: 9605 AN: 49002

GnomAD4 genome AF: 0.155 AC: 23505 AN: 151844 Hom.: 2246 Cov.: 32 AF XY: 0.150 AC XY: 11170 AN XY: 74238

African (AFR) AF: 0.0484 AC: 2007 AN: 41442

American (AMR) AF: 0.166 AC: 2522 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 968 AN: 3468

East Asian (EAS) AF: 0.177 AC: 915 AN: 5168

South Asian (SAS) AF: 0.156 AC: 749 AN: 4816

European-Finnish (FIN) AF: 0.117 AC: 1233 AN: 10538

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.212 AC: 14393 AN: 67888

Other (OTH) AF: 0.194 AC: 410 AN: 2110

Alfa AF: 0.163 Hom.: 305

Bravo AF: 0.156

Asia WGS AF: 0.141 AC: 494 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.059
DANN	Benign	0.81
PhyloP100		-1.6
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: rs11175966; hg19: chr12-40703152;