rs78964014

Variant names:

• chr12-40364843-G-A
• rs78964014
• NM_198578.4:c.7183G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_198578.4(LRRK2):​c.7183G>A​(p.Glu2395Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,452,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: LRRK2 NM_198578.4 missense, splice_region
• Scores: Splicing: ADA: 0.005951
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 3.14

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 Likely_benign. Variant got -3 ACMG points.

• PM1: In a mutagenesis_site Decreases WD domain homodimerization. No effect on kinase activity. (size 0) in uniprot entity LRRK2_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.40001613).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4	c.7183G>A	p.Glu2395Lys	missense_variant, splice_region_variant	Exon 49 of 51	ENST00000298910.12	NP_940980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12	c.7183G>A	p.Glu2395Lys	missense_variant, splice_region_variant	Exon 49 of 51	1	NM_198578.4	ENSP00000298910.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000482 AC: 7 AN: 1452788 Hom.: 0 Cov.: 27 AF XY: 0.00000415 AC XY: 3 AN XY: 723274

Gnomad4 AFR exome AF: 0.0000301

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: 0.00000543

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Autosomal dominant Parkinson disease 8 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.17
Sift	Benign	0.23	T
Sift4G	Benign	0.20	T
Polyphen		0.70	P
Vest4		0.45
MutPred		0.41		Gain of methylation at E2395 (P = 0.0061);
MVP		0.93
MPC		0.35
ClinPred		0.84	D
GERP RS		5.4
Varity_R		0.49
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0060
dbscSNV1_RF	Benign	0.088
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs78964014; hg19: chr12-40758645;