rs376015112
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_198578.4(LRRK2):c.2314C>T(p.Arg772*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000070 ( 0 hom. )
Consequence
LRRK2
NM_198578.4 stop_gained
NM_198578.4 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.01
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAdExome4 at 103 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LRRK2 | NM_198578.4 | c.2314C>T | p.Arg772* | stop_gained | 19/51 | ENST00000298910.12 | NP_940980.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LRRK2 | ENST00000298910.12 | c.2314C>T | p.Arg772* | stop_gained | 19/51 | 1 | NM_198578.4 | ENSP00000298910.7 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 151960Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251092Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135674
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GnomAD4 exome AF: 0.0000705 AC: 103AN: 1461556Hom.: 0 Cov.: 31 AF XY: 0.0000605 AC XY: 44AN XY: 727060
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 151960Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74208
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal dominant Parkinson disease 8 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 16, 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. ClinVar contains an entry for this variant (Variation ID: 236290). This premature translational stop signal has been observed in individual(s) with Parkinson disease (PMID: 26213354). This variant is present in population databases (rs376015112, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg772*) in the LRRK2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in LRRK2 cause disease. - |
Uncertain significance, no assertion criteria provided | literature only | GeneReviews | Dec 11, 2014 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
0.97, 0.99
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at