rs75148313

chr12-40295466-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_198578.4(LRRK2):c.2918G>A(p.Ser973Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LRRK2 NM_198578.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 5.42

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity LRRK2_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.24432394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRK2	NM_198578.4	c.2918G>A	p.Ser973Asn	missense_variant	23/51	ENST00000298910.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRK2	ENST00000298910.12	c.2918G>A	p.Ser973Asn	missense_variant	23/51	1	NM_198578.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250554 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461328 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726946

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Uncertain:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 26, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change does not substantially affect LRRK2 function (PMID: 20642453, 35950872). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LRRK2 protein function. ClinVar contains an entry for this variant (Variation ID: 39158). This missense change has been observed in individual(s) with Parkinson disease (PMID: 17523199, 21885347). This variant is present in population databases (rs75148313, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 973 of the LRRK2 protein (p.Ser973Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.028	T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.13
Sift	Benign	0.14	T;T
Sift4G	Pathogenic	0.0	D;T
Polyphen		0.91	P;D
Vest4		0.65
MutPred		0.12		Loss of phosphorylation at S973 (P = 0.0073);Loss of phosphorylation at S973 (P = 0.0073);
MVP		0.80
MPC		0.46
ClinPred		0.90	D
GERP RS		4.8
Varity_R		0.19
gMVP		0.26

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: rs75148313; hg19: chr12-40689268; COSMIC: COSV100110944; COSMIC: COSV100110944;