rs201739149

Variant names:

• chr12-40302773-AT-A
• rs201739149
• NM_198578.4:c.3497-8delT

Your query was ambiguous. Multiple possible variants found:

• chr12-40302773-AT-A
• chr12-40302773-AT-ATT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_198578.4(LRRK2):​c.3497-8delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,518,106 control chromosomes in the GnomAD database, including 71 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (20 hom.)
• Consequence: LRRK2 NM_198578.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.158
• Publications: 0 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-40302773-AT-A is Benign according to our data. Variant chr12-40302773-AT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 308626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1863/151728) while in subpopulation AFR AF = 0.0392 (1624/41432). AF 95% confidence interval is 0.0376. There are 51 homozygotes in GnomAd4. There are 863 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1863 AD gene.

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.3497-8delT		splice_region 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.3497-15delT		intron	N/A	ENSP00000298910.7
	LRRK2	ENST00000430804.5	TSL:1	n.*170-15delT		intron	N/A	ENSP00000410821.1
	LRRK2	ENST00000680790.1		c.3242-15delT		intron	N/A	ENSP00000505335.1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1862 AN: 151612 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00934

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000708

Gnomad OTH AF: 0.0121

GnomAD2 exomes AF: 0.00358 AC: 881 AN: 245896 AF XY: 0.00284

Gnomad AFR exome AF: 0.0400

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.00414

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000770

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.00192 AC: 2620 AN: 1366378 Hom.: 20 Cov.: 24 AF XY: 0.00173 AC XY: 1188 AN XY: 685484

African (AFR) AF: 0.0401 AC: 1264 AN: 31492

American (AMR) AF: 0.00330 AC: 147 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00439 AC: 112 AN: 25500

East Asian (EAS) AF: 0.00 AC: 0 AN: 38972

South Asian (SAS) AF: 0.000974 AC: 82 AN: 84204

European-Finnish (FIN) AF: 0.0000943 AC: 5 AN: 53006

Middle Eastern (MID) AF: 0.00308 AC: 17 AN: 5526

European-Non Finnish (NFE) AF: 0.000750 AC: 769 AN: 1026002

Other (OTH) AF: 0.00392 AC: 224 AN: 57178

GnomAD4 genome AF: 0.0123 AC: 1863 AN: 151728 Hom.: 51 Cov.: 32 AF XY: 0.0116 AC XY: 863 AN XY: 74180

African (AFR) AF: 0.0392 AC: 1624 AN: 41432

American (AMR) AF: 0.00933 AC: 142 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3464

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000708 AC: 48 AN: 67762

Other (OTH) AF: 0.0119 AC: 25 AN: 2094

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.0145

Asia WGS AF: 0.00145 AC: 5 AN: 3468

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal dominant Parkinson disease 8 (3)
-	-	2	not provided (2)
-	-	1	LRRK2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism

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: rs201739149; hg19: chr12-40696575; COSMIC: COSV100111382;