rs2404834

Variant names:

• chr12-40335205-C-T
• rs2404834
• NM_198578.4:c.5948+48C>T

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.5948+48C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,594,976 control chromosomes in the GnomAD database, including 16,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1713 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14895 hom.)
• Consequence: LRRK2 NM_198578.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.520
• Publications: 10 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=-0.89).
• BP6: Variant 12-40335205-C-T is Benign according to our data. Variant chr12-40335205-C-T is described in ClinVar as Benign. ClinVar VariationId is 1250743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 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.5948+48C>T		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.5948+48C>T		intron	N/A	ENSP00000298910.7
	LRRK2	ENST00000430804.5	TSL:1	n.*2621+48C>T		intron	N/A	ENSP00000410821.1
	LRRK2	ENST00000680790.1		c.5693+48C>T		intron	N/A	ENSP00000505335.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21385 AN: 151990 Hom.: 1710 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.0931

Gnomad ASJ AF: 0.0720

Gnomad EAS AF: 0.0258

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.122 AC: 29498 AN: 242070 AF XY: 0.119

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.0790

Gnomad ASJ exome AF: 0.0697

Gnomad EAS exome AF: 0.0261

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.136 AC: 196946 AN: 1442868 Hom.: 14895 Cov.: 27 AF XY: 0.134 AC XY: 96050 AN XY: 718286

African (AFR) AF: 0.156 AC: 5159 AN: 33076

American (AMR) AF: 0.0794 AC: 3495 AN: 44010

Ashkenazi Jewish (ASJ) AF: 0.0698 AC: 1808 AN: 25900

East Asian (EAS) AF: 0.0301 AC: 1191 AN: 39520

South Asian (SAS) AF: 0.0390 AC: 3324 AN: 85268

European-Finnish (FIN) AF: 0.252 AC: 13371 AN: 53052

Middle Eastern (MID) AF: 0.100 AC: 575 AN: 5722

European-Non Finnish (NFE) AF: 0.146 AC: 160086 AN: 1096594

Other (OTH) AF: 0.133 AC: 7937 AN: 59726

GnomAD4 genome AF: 0.141 AC: 21397 AN: 152108 Hom.: 1713 Cov.: 32 AF XY: 0.143 AC XY: 10659 AN XY: 74342

African (AFR) AF: 0.151 AC: 6258 AN: 41486

American (AMR) AF: 0.0928 AC: 1420 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0720 AC: 250 AN: 3472

East Asian (EAS) AF: 0.0261 AC: 135 AN: 5180

South Asian (SAS) AF: 0.0290 AC: 140 AN: 4826

European-Finnish (FIN) AF: 0.266 AC: 2811 AN: 10558

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9886 AN: 67978

Other (OTH) AF: 0.127 AC: 267 AN: 2106

Alfa AF: 0.136 Hom.: 2585

Bravo AF: 0.129

Asia WGS AF: 0.0440 AC: 155 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	-0.89
CADD	Benign	0.35
DANN	Benign	0.71
PhyloP100		-0.52
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: rs2404834; hg19: chr12-40729007; COSMIC: COSV54169614;