rs7308720

Variant names:

• chr12-40263898-C-G
• rs7308720
• NM_198578.4:c.1653C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-40263898-C-G
• chr12-40263898-C-T
• chr12-40263898-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_198578.4(LRRK2):​c.1653C>G​(p.Asn551Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0742 in 1,596,920 control chromosomes in the GnomAD database, including 5,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N551N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.098 (892 hom., cov: 32)
  • Exomes 𝑓: 0.072 (4312 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: 0.392
• Publications: 117 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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017452538).
• BP6: Variant 12-40263898-C-G is Benign according to our data. Variant chr12-40263898-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 39139.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.155 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.1653C>G	p.Asn551Lys	missense	Exon 14 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.1653C>G	p.Asn551Lys	missense	Exon 14 of 51	ENSP00000298910.7	Q5S007
	LRRK2	ENST00000950031.1		c.1629C>G	p.Asn543Lys	missense	Exon 14 of 51	ENSP00000620090.1
	LRRK2	ENST00000680790.1		c.1398C>G	p.Asn466Lys	missense	Exon 12 of 49	ENSP00000505335.1	A0A7P0T8S1

Frequencies

GnomAD3 genomes AF: 0.0976 AC: 14840 AN: 152000 Hom.: 888 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.0555

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0685

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.0868 AC: 21777 AN: 250972 AF XY: 0.0806

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.0948

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.0559

Gnomad NFE exome AF: 0.0720

Gnomad OTH exome AF: 0.0758

GnomAD4 exome AF: 0.0717 AC: 103567 AN: 1444802 Hom.: 4312 Cov.: 28 AF XY: 0.0701 AC XY: 50487 AN XY: 719822

African (AFR) AF: 0.136 AC: 4502 AN: 33038

American (AMR) AF: 0.163 AC: 7283 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.0951 AC: 2472 AN: 25990

East Asian (EAS) AF: 0.125 AC: 4921 AN: 39490

South Asian (SAS) AF: 0.0388 AC: 3329 AN: 85730

European-Finnish (FIN) AF: 0.0576 AC: 3071 AN: 53292

Middle Eastern (MID) AF: 0.0510 AC: 291 AN: 5706

European-Non Finnish (NFE) AF: 0.0666 AC: 73083 AN: 1097180

Other (OTH) AF: 0.0772 AC: 4615 AN: 59748

GnomAD4 genome AF: 0.0977 AC: 14861 AN: 152118 Hom.: 892 Cov.: 32 AF XY: 0.0984 AC XY: 7319 AN XY: 74356

African (AFR) AF: 0.141 AC: 5849 AN: 41504

American (AMR) AF: 0.160 AC: 2441 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 356 AN: 3470

East Asian (EAS) AF: 0.100 AC: 518 AN: 5178

South Asian (SAS) AF: 0.0422 AC: 203 AN: 4816

European-Finnish (FIN) AF: 0.0555 AC: 587 AN: 10578

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0685 AC: 4658 AN: 67990

Other (OTH) AF: 0.102 AC: 215 AN: 2114

Alfa AF: 0.0747 Hom.: 352

Bravo AF: 0.109

TwinsUK AF: 0.0639 AC: 237

ALSPAC AF: 0.0638 AC: 246

ESP6500AA AF: 0.138 AC: 609

ESP6500EA AF: 0.0722 AC: 621

ExAC AF: 0.0858 AC: 10422

Asia WGS AF: 0.0740 AC: 257 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Autosomal dominant Parkinson disease 8 (5)
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.39
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.25
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.88	P
Vest4		0.33
MutPred		0.57		Gain of MoRF binding (P = 0.034)
MPC		0.49
ClinPred		0.038	T
GERP RS		2.7
Varity_R		0.43
gMVP		0.63
Mutation Taster		=64/36	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: rs7308720; hg19: chr12-40657700; COSMIC: COSV54152785;