rs10878371

Variant names:

• chr12-40322458-T-C
• rs10878371
• NM_198578.4:c.5457T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-40322458-T-C
• chr12-40322458-T-G
• chr12-40322458-T-A

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.5457T>C​(p.Gly1819Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,612,358 control chromosomes in the GnomAD database, including 252,740 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. G1819G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.57 (24464 hom., cov: 31)
  • Exomes 𝑓: 0.56 (228276 hom.)
• Consequence: LRRK2 NM_198578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.506
• Publications: 40 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: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 12-40322458-T-C is Benign according to our data. Variant chr12-40322458-T-C is described in ClinVar as Benign. ClinVar VariationId is 39209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.506 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.676 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.5457T>C	p.Gly1819Gly	synonymous	Exon 37 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.5457T>C	p.Gly1819Gly	synonymous	Exon 37 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000430804.5	TSL:1	n.*2130T>C		non_coding_transcript_exon	Exon 16 of 30	ENSP00000410821.1	H7C3B6
	LRRK2	ENST00000430804.5	TSL:1	n.*2130T>C		3_prime_UTR	Exon 16 of 30	ENSP00000410821.1	H7C3B6

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85848 AN: 151542 Hom.: 24447 Cov.: 31

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.630

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.557

GnomAD2 exomes AF: 0.577 AC: 144889 AN: 251196 AF XY: 0.577

Gnomad AFR exome AF: 0.586

Gnomad AMR exome AF: 0.664

Gnomad ASJ exome AF: 0.553

Gnomad EAS exome AF: 0.477

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.545

Gnomad OTH exome AF: 0.564

GnomAD4 exome AF: 0.557 AC: 813102 AN: 1460698 Hom.: 228276 Cov.: 42 AF XY: 0.560 AC XY: 406709 AN XY: 726706

African (AFR) AF: 0.586 AC: 19590 AN: 33456

American (AMR) AF: 0.659 AC: 29476 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 14474 AN: 26106

East Asian (EAS) AF: 0.479 AC: 18979 AN: 39630

South Asian (SAS) AF: 0.688 AC: 59347 AN: 86218

European-Finnish (FIN) AF: 0.540 AC: 28831 AN: 53396

Middle Eastern (MID) AF: 0.502 AC: 2893 AN: 5762

European-Non Finnish (NFE) AF: 0.545 AC: 605644 AN: 1111066

Other (OTH) AF: 0.561 AC: 33868 AN: 60352

GnomAD4 genome AF: 0.566 AC: 85915 AN: 151660 Hom.: 24464 Cov.: 31 AF XY: 0.569 AC XY: 42136 AN XY: 74094

African (AFR) AF: 0.587 AC: 24314 AN: 41420

American (AMR) AF: 0.630 AC: 9593 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1916 AN: 3462

East Asian (EAS) AF: 0.480 AC: 2473 AN: 5148

South Asian (SAS) AF: 0.695 AC: 3351 AN: 4820

European-Finnish (FIN) AF: 0.530 AC: 5569 AN: 10508

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 36940 AN: 67770

Other (OTH) AF: 0.555 AC: 1171 AN: 2110

Alfa AF: 0.553 Hom.: 17190

Bravo AF: 0.570

Asia WGS AF: 0.590 AC: 2048 AN: 3478

EpiCase AF: 0.540

EpiControl AF: 0.536

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.3
DANN	Benign	0.67
PhyloP100		-0.51
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: rs10878371; hg19: chr12-40716260; COSMIC: COSV54146503; COSMIC: COSV54146503;