12-40338592-T-C

Variant names:

• chr12-40338592-T-C
• rs1427271
• NM_198578.4:c.5949-1702T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198578.4(LRRK2):​c.5949-1702T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 152,144 control chromosomes in the GnomAD database, including 45,723 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 0.77 (45723 hom., cov: 33)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.170
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.849 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.5949-1702T>C		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.5949-1702T>C		intron	N/A	ENSP00000298910.7
	LRRK2	ENST00000430804.5	TSL:1	n.*2622-1702T>C		intron	N/A	ENSP00000410821.1
	LRRK2	ENST00000680790.1		c.5694-1702T>C		intron	N/A	ENSP00000505335.1

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116766 AN: 152026 Hom.: 45699 Cov.: 33

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.737

Gnomad ASJ AF: 0.824

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.758

Gnomad FIN AF: 0.870

Gnomad MID AF: 0.834

Gnomad NFE AF: 0.855

Gnomad OTH AF: 0.774

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.768 AC: 116842 AN: 152144 Hom.: 45723 Cov.: 33 AF XY: 0.767 AC XY: 57057 AN XY: 74382

African (AFR) AF: 0.618 AC: 25617 AN: 41482

American (AMR) AF: 0.737 AC: 11253 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 2861 AN: 3472

East Asian (EAS) AF: 0.658 AC: 3407 AN: 5174

South Asian (SAS) AF: 0.757 AC: 3649 AN: 4820

European-Finnish (FIN) AF: 0.870 AC: 9236 AN: 10614

Middle Eastern (MID) AF: 0.836 AC: 244 AN: 292

European-Non Finnish (NFE) AF: 0.855 AC: 58146 AN: 67986

Other (OTH) AF: 0.775 AC: 1640 AN: 2116

Alfa AF: 0.830 Hom.: 26585

Bravo AF: 0.749

Asia WGS AF: 0.673 AC: 2322 AN: 3448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		0.17
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: rs1427271; hg19: chr12-40732394;