chr12-40294893-T-C

Variant names:

• chr12-40294893-T-C
• rs7966550
• NM_198578.4:c.2857T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198578.4(LRRK2):​c.2857T>C​(p.Leu953Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,543,352 control chromosomes in the GnomAD database, including 9,795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L953L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.092 (796 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8999 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.974
• Publications: 28 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-40294893-T-C is Benign according to our data. Variant chr12-40294893-T-C is described in ClinVar as Benign. ClinVar VariationId is 39156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.974 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	NM_198578.4	MANE Select	c.2857T>C	p.Leu953Leu	synonymous	Exon 22 of 51	NP_940980.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRK2	ENST00000298910.12	TSL:1 MANE Select	c.2857T>C	p.Leu953Leu	synonymous	Exon 22 of 51	ENSP00000298910.7
	LRRK2	ENST00000950031.1		c.2833T>C	p.Leu945Leu	synonymous	Exon 22 of 51	ENSP00000620090.1
	LRRK2	ENST00000680790.1		c.2602T>C	p.Leu868Leu	synonymous	Exon 20 of 49	ENSP00000505335.1

Frequencies

GnomAD3 genomes AF: 0.0916 AC: 13926 AN: 151954 Hom.: 796 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.0619

Gnomad FIN AF: 0.0820

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.104 AC: 26057 AN: 249754 AF XY: 0.105

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.0832

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.181

Gnomad FIN exome AF: 0.0820

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.109 AC: 151772 AN: 1391280 Hom.: 8999 Cov.: 24 AF XY: 0.108 AC XY: 75102 AN XY: 694816

African (AFR) AF: 0.0206 AC: 667 AN: 32376

American (AMR) AF: 0.0866 AC: 3837 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2853 AN: 25458

East Asian (EAS) AF: 0.156 AC: 6074 AN: 38934

South Asian (SAS) AF: 0.0610 AC: 5042 AN: 82600

European-Finnish (FIN) AF: 0.0828 AC: 4343 AN: 52468

Middle Eastern (MID) AF: 0.126 AC: 632 AN: 5022

European-Non Finnish (NFE) AF: 0.116 AC: 122268 AN: 1052314

Other (OTH) AF: 0.105 AC: 6056 AN: 57782

GnomAD4 genome AF: 0.0916 AC: 13932 AN: 152072 Hom.: 796 Cov.: 32 AF XY: 0.0897 AC XY: 6669 AN XY: 74352

African (AFR) AF: 0.0255 AC: 1060 AN: 41554

American (AMR) AF: 0.112 AC: 1710 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 383 AN: 3466

East Asian (EAS) AF: 0.156 AC: 811 AN: 5184

South Asian (SAS) AF: 0.0621 AC: 299 AN: 4814

European-Finnish (FIN) AF: 0.0820 AC: 867 AN: 10572

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.124 AC: 8399 AN: 67918

Other (OTH) AF: 0.110 AC: 232 AN: 2110

Alfa AF: 0.111 Hom.: 2162

Bravo AF: 0.0940

Asia WGS AF: 0.102 AC: 355 AN: 3460

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal dominant Parkinson disease 8 (4)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.60
PhyloP100		-0.97
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: rs7966550; hg19: chr12-40688695; COSMIC: COSV54147703; COSMIC: COSV54147703;