rs34778348

Positions:

• chr12-40363526-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_198578.4(LRRK2):​c.7153G>A​(p.Gly2385Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000787 in 1,611,766 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars). Synonymous variant affecting the same amino acid position (i.e. G2385G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00084 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (22 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:1 U:2 B:2 O:3
• Conservation: PhyloP100: 5.68

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]

LOC105369736 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067643523).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000836 (127/151964) while in subpopulation EAS AF= 0.0238 (123/5162). AF 95% confidence interval is 0.0204. There are 5 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.7153G>A	p.Gly2385Arg	missense_variant	48/51	ENST00000298910.12
LOC105369736	XR_944868.3	n.485-8699C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.7153G>A	p.Gly2385Arg	missense_variant	48/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes AF: 0.000823 AC: 125 AN: 151846 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0234

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00171 AC: 429 AN: 250734 Hom.: 7 AF XY: 0.00170 AC XY: 231 AN XY: 135518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0218

Gnomad SAS exome AF: 0.000556

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.000782 AC: 1142 AN: 1459802 Hom.: 22 Cov.: 33 AF XY: 0.000819 AC XY: 595 AN XY: 726230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0266

Gnomad4 SAS exome AF: 0.000534

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000481

GnomAD4 genome AF: 0.000836 AC: 127 AN: 151964 Hom.: 5 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74286

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0238

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00136 Hom.: 7

Bravo AF: 0.00105

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00158 AC: 192

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity; risk factor

Submissions summary: Pathogenic:1 Uncertain:2 Benign:2 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Pathogenic:1 Uncertain:1 Benign:2 Other:2

risk factor, no assertion criteria provided	literature only	OMIM	Oct 01, 2008	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Pathogenic, flagged submission	provider interpretation	Codex Genetics Limited	Feb 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Apr 09, 2020

- -

Parkinson disease Other:1

risk factor, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 21, 2020

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.044
Sift	Benign	0.19	T
Sift4G	Uncertain	0.032	D
Polyphen		0.074	B
Vest4		0.37
MutPred		0.42		Gain of MoRF binding (P = 0.0773);
MVP		0.70
MPC		0.24
ClinPred		0.045	T
GERP RS		4.4
Varity_R		0.34
gMVP		0.36

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: rs34778348; hg19: chr12-40757328; COSMIC: COSV54154420;