rs35808389
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_198578.4(LRRK2):āc.3342A>Gā(p.Leu1114=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,613,822 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 Likely benign (ā ā ).
Frequency
Genomes: š 0.00016 ( 0 hom., cov: 31)
Exomes š: 0.00021 ( 0 hom. )
Consequence
LRRK2
NM_198578.4 synonymous
NM_198578.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.612
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 Benign. Variant got -17 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.57).
BP6
?
Variant 12-40298488-A-G is Benign according to our data. Variant chr12-40298488-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 39164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40298488-A-G is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=0.612 with no splicing effect.
BS2
?
High AC in GnomAd4 at 24 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRRK2 | NM_198578.4 | c.3342A>G | p.Leu1114= | synonymous_variant | 24/51 | ENST00000298910.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRRK2 | ENST00000298910.12 | c.3342A>G | p.Leu1114= | synonymous_variant | 24/51 | 1 | NM_198578.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152076Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000207 AC: 52AN: 251264Hom.: 0 AF XY: 0.000214 AC XY: 29AN XY: 135794
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GnomAD4 exome AF: 0.000212 AC: 310AN: 1461746Hom.: 0 Cov.: 32 AF XY: 0.000204 AC XY: 148AN XY: 727176
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GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152076Hom.: 0 Cov.: 31 AF XY: 0.0000808 AC XY: 6AN XY: 74270
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 11, 2020 | This variant is associated with the following publications: (PMID: 31589614, 21885347, 15541309, 16157908, 17523199, 17415511, 16616379) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | LRRK2: BP4, BP7 - |
Autosomal dominant Parkinson disease 8 Benign:1Other:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Apr 22, 2023 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 12, 2021 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 18, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
LRRK2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 22, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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