rs28903073

Variant names:

• chr12-40259708-G-A
• rs28903073
• NM_198578.4:c.1543+104G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_198578.4(LRRK2):​c.1543+104G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,417,634 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (16 hom.)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.101
• Publications: 8 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High AC in GnomAd4 at 371 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.1543+104G>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.1543+104G>A		intron	N/A	ENSP00000298910.7
	LRRK2	ENST00000680790.1		c.1289-4081G>A		intron	N/A	ENSP00000505335.1
	LRRK2	ENST00000343742.6	TSL:5	c.1543+104G>A		intron	N/A	ENSP00000341930.2

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 371 AN: 152152 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00413

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00346

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00320 AC: 4043 AN: 1265364 Hom.: 16 AF XY: 0.00330 AC XY: 2104 AN XY: 638130

African (AFR) AF: 0.000622 AC: 18 AN: 28948

American (AMR) AF: 0.00123 AC: 52 AN: 42130

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 339 AN: 24234

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37794

South Asian (SAS) AF: 0.00424 AC: 340 AN: 80184

European-Finnish (FIN) AF: 0.000426 AC: 19 AN: 44582

Middle Eastern (MID) AF: 0.00715 AC: 36 AN: 5032

European-Non Finnish (NFE) AF: 0.00324 AC: 3074 AN: 948950

Other (OTH) AF: 0.00306 AC: 164 AN: 53510

GnomAD4 genome AF: 0.00244 AC: 371 AN: 152270 Hom.: 1 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74450

African (AFR) AF: 0.000938 AC: 39 AN: 41562

American (AMR) AF: 0.00157 AC: 24 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4834

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00346 AC: 235 AN: 68006

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00306 Hom.: 0

Bravo AF: 0.00253

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.6
DANN	Benign	0.42
PhyloP100		0.10
Mutation Taster		=99/1	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: rs28903073; hg19: chr12-40653510;