BA1 (stand-alone benign) is met: NM_198578.3:c.4229C>T (p.Thr1410Met) has an allele frequency of 2.12% in the African/African American population in gnomAD v2.1 (528/24,960 alleles, 6 homozygotes) and 2.07% in v4.1 (1,552/74,966 alleles, 17 homozygotes), which far exceeds the prevalence of autosomal dominant LRRK2-related Parkinson's disease and meets the >1% BA1 threshold.1 BS1 (strong benign) is independently met: the overall gnomAD v2.1 allele frequency of 0.21% and the African subpopulation frequency of 2.12% exceed the >0.3% BS1 threshold. This frequency is inconsistent with a pathogenic role in Parkinson's disease.2 BS2 (supporting benign) is met: 6 homozygous individuals are observed in gnomAD v2.1 and 18 in v4.1, consistent with a benign variant tolerated in the homozygous state.3 BP4 (supporting benign) is met: computational predictors REVEL (0.466), BayesDel (-0.172832), and SpliceAI (max delta 0.15) do not predict a damaging effect.4 BP6 (supporting benign) is met: ClinVar reports the variant as Benign (3 clinical laboratories) and Likely benign (2 clinical laboratories).5 Final classification: Benign. BA1 alone is sufficient for a Benign classification per ACMG/AMP 2015 rules. Additional supporting benign criteria (BS1, BS2, BP4, BP6) reinforce this determination.6
LRRK2
Final classification
Benign
LRRK2 c.4229C>T · p.Thr1410Met
LRRK2
BA1 (stand-alone benign) is met: NM_198578.3:c.4229C>T (p.Thr1410Met) has an allele frequency of 2.12% in the African/African American population in gnomAD v2.1 (528/24,960 alleles, 6 homozygotes) and 2.07% in v4.1 (1,552/74,966 alleles, 17 homozygotes), which far exceeds the prevalence of autosomal dominant LRRK2-related Parkinson's disease and meets the >1% BA1 threshold.
ClinGen Parkinson's Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LRRK2 Version 1.0.0 v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BS2 supporting benign, BP4 supporting benign, BP6 supporting benign; combination = 1 stand-alone benign + 1 strong benign + 3 supporting benign, which maps to Benign.
Classification rationale
BA1BS1BS2BP4BP6
Benign
LRRK2 c.4229C>T
BA1 + BS1 + BS2 + BP4 + BP6
→
Benign
4
revelbayesdelspliceai ↗
6
generic_acmg_combination_rules
Gene diagram
· NM_198578.3 · variants mapped to exon structure
LRRK2
NM_198578.3
Fetching transcript structure from UCSC…
Applied criteria · 5 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00115883; MAF= 0.11588%, 1870/1613692 alleles, homozygotes = 18) and has highest observed frequency in the African/African American population (AF= 0.0207027; MAF= 2.07027%, 1552/74966 alleles, homozygotes = 17); grpmax FAF= 0.0198454.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00209907; MAF= 0.20991%, 593/282506 alleles, homozygotes = 6) and has highest observed frequency in the African/African American population (AF= 0.0211538; MAF= 2.11538%, 528/24960 alleles, homozygotes = 6); grpmax FAF= 0.020734.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0014115092290988057, 26/18420 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.12%
· 1870 / 1,613,692
18 hom · FAF 2%
18 hom · FAF 2%
African/African American 1552 / 74,966 |
2.1% 17 hom |
Remaining individuals 97 / 62,480 |
0.16% 1 hom |
Admixed American 79 / 59,978 |
0.13% |
Middle Eastern 3 / 6,058 |
0.05% |
South Asian 40 / 91,060 |
0.044% |
European (non-Finnish) 97 / 1,179,816 |
0.0082% |
East Asian 2 / 44,868 |
0.0045% |
+ 3 not observed (European (Finnish), Amish, Ashkenazi Jewish)
gnomAD v2.1
0.21%
· 593 / 282,506
6 hom · FAF 2.1%
6 hom · FAF 2.1%
African/African American 528 / 24,960 |
2.1% 6 hom |
Admixed American 30 / 35,404 |
0.085% |
Remaining individuals 6 / 7,204 |
0.083% |
South Asian 15 / 30,610 |
0.049% |
European (non-Finnish) 13 / 128,886 |
0.01% |
East Asian 1 / 19,952 |
0.005% |
+ 2 not observed (Ashkenazi Jewish, European (Finnish))
gnomAD Canada 🇨🇦
0.14%
· 26 / 18,420
0 hom · FAF 1.5%
0 hom · FAF 1.5%
African/African American 23 / 1,020 |
2.3% |
Latino/Admixed American 1 / 838 |
0.12% |
Remaining individuals 1 / 1,138 |
0.088% |
European (non-Finnish) 1 / 11,740 |
0.0085% |
+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, South Asian)
ClinVar
This variant has been reported in ClinVar as Benign (3 clinical laboratories) and as Likely benign (2 clinical laboratories). (ClinVarID = 39179)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). REVEL score = 0.466. BayesDel score = -0.172832.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV114383285, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 7 PMIDs not cited in assessment
20443975 ↗
Genetic analysis of LRRK2 functional domains in Brazilian patients with Parkinson's disease.
CLINVAR
21060682 ↗
Identification and characterization of a leucine-rich repeat kinase 2 (LRRK2) consensus phosphorylation motif.
CLINVAR
23279440 ↗
EFNS/MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson's disease.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR