NM_198578.4:c.2167A>G

Variant names:

• chr12-40278187-A-G
• rs10878307
• NM_198578.4:c.2167A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198578.4(LRRK2):​c.2167A>G​(p.Ile723Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0644 in 1,614,076 control chromosomes in the GnomAD database, including 3,947 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (246 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3701 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.654

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012659132).
• BP6: Variant 12-40278187-A-G is Benign according to our data. Variant chr12-40278187-A-G is described in ClinVar as [Benign]. Clinvar id is 39146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40278187-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.076 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.2167A>G	p.Ile723Val	missense_variant	Exon 18 of 51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.2167A>G	p.Ile723Val	missense_variant	Exon 18 of 51	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes AF: 0.0487 AC: 7417 AN: 152208 Hom.: 248 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0425

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.00923

Gnomad SAS AF: 0.0834

Gnomad FIN AF: 0.0264

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.0700

Gnomad OTH AF: 0.0698

GnomAD3 exomes AF: 0.0585 AC: 14694 AN: 251266 Hom.: 637 AF XY: 0.0633 AC XY: 8590 AN XY: 135788

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.0351

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.00397

Gnomad SAS exome AF: 0.0848

Gnomad FIN exome AF: 0.0275

Gnomad NFE exome AF: 0.0720

Gnomad OTH exome AF: 0.0700

GnomAD4 exome AF: 0.0661 AC: 96605 AN: 1461750 Hom.: 3701 Cov.: 32 AF XY: 0.0674 AC XY: 48998 AN XY: 727176

Gnomad4 AFR exome AF: 0.0108

Gnomad4 AMR exome AF: 0.0374

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.0226

Gnomad4 SAS exome AF: 0.0844

Gnomad4 FIN exome AF: 0.0305

Gnomad4 NFE exome AF: 0.0685

Gnomad4 OTH exome AF: 0.0670

GnomAD4 genome AF: 0.0486 AC: 7409 AN: 152326 Hom.: 246 Cov.: 32 AF XY: 0.0466 AC XY: 3469 AN XY: 74498

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.0425

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.00925

Gnomad4 SAS AF: 0.0826

Gnomad4 FIN AF: 0.0264

Gnomad4 NFE AF: 0.0700

Gnomad4 OTH AF: 0.0691

Alfa AF: 0.0702 Hom.: 1155

Bravo AF: 0.0479

TwinsUK AF: 0.0688 AC: 255

ALSPAC AF: 0.0714 AC: 275

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.0714 AC: 614

ExAC AF: 0.0592 AC: 7189

Asia WGS AF: 0.0310 AC: 106 AN: 3478

EpiCase AF: 0.0798

EpiControl AF: 0.0801

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Benign:2 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Aug 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.7
DANN	Benign	0.61
DEOGEN2	Benign	0.027	.;T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.71	T;T;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	.;.;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.020	N;N;N
REVEL	Benign	0.045
Sift	Benign	0.68	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0010, 0.0	.;B;B
Vest4		0.046, 0.076
MPC		0.072
ClinPred		0.0030	T
GERP RS		-0.91
Varity_R		0.025
gMVP		0.079

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: rs10878307; hg19: chr12-40671989;