rs28903073

Positions:

• chr12-40259708-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High AC in GnomAd4 at 371 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.1543+104G>A		intron_variant		ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.1543+104G>A		intron_variant		1	NM_198578.4	ENSP00000298910	P1

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

Gnomad4 AFR exome AF: 0.000622

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.0000265

Gnomad4 SAS exome AF: 0.00424

Gnomad4 FIN exome AF: 0.000426

Gnomad4 NFE exome AF: 0.00324

Gnomad4 OTH exome AF: 0.00306

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

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00346

Gnomad4 OTH AF: 0.00284

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.6
DANN	Benign	0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs28903073; hg19: chr12-40653510;