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 applied · 16 assessed
Applied · 5
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
This variant has an allele frequency >1% in the African/African American population of gnomAD. gnomAD v2.1: AF=2.12% (528/24,960 alleles, 6 homozygotes). gnomAD v4.1: AF=2.07% (1,552/74,966 alleles, 17 homozygotes). This frequency far exceeds the prevalence of autosomal dominant LRRK2-related Parkinson's disease, meeting BA1 (stand-alone benign).
gnomAD v2.1 African AF=2.12% (>1% BA1 threshold)v4.1 African AF=2.07% (>1% BA1 threshold)multiple homozygotes observed
✓
BS1
strong
Benign
This variant has an allele frequency >0.3% in the general gnomAD v2.1 population (0.21%) and substantially exceeds this threshold in the African/African American subpopulation (2.12%). The variant's frequency is greater than expected for an autosomal dominant Parkinson's disease-causing variant. BS1 is superseded by BA1 in the classification but is independently met.
gnomAD v2.1 overall AF=0.21%African AF=2.12% (>>0.3% BS1 threshold)v4.1 overall AF=0.12%
✓
BS2
supporting
Benign
This variant is observed in 6 apparently healthy homozygous individuals in gnomAD v2.1 and 18 homozygotes in gnomAD v4.1. While Parkinson's disease is late-onset, the presence of multiple homozygotes in a population database without reported early-onset parkinsonism is consistent with a benign interpretation.
6 homozygotes in gnomAD v2.118 homozygotes in gnomAD v4.1observation of homozygotes in a population database supports benign interpretation
✓
BP4
supporting
Benign
Multiple lines of computational evidence support a benign interpretation: REVEL score 0.466 (below 0.5 threshold), BayesDel score -0.172832 (below 0.13 damaging threshold), and SpliceAI max delta 0.15 (no predicted splice impact). The aggregate in silico evidence does not predict a damaging effect on the gene product.
REVEL=0.466BayesDel=-0.172832 (benign)SpliceAI max delta=0.15 (no splice impact)
✓
BP6
supporting
Benign
This variant has been classified as Benign by 3 clinical laboratories and Likely benign by 2 clinical laboratories in ClinVar (ClinVar variation ID 39179). Multiple submitters with consistent benign classifications constitute a reputable source for BP6. Submitting laboratories include Labcorp Genetics (formerly Invitae), Illumina Laboratory Services, and Breakthrough Genomics.
ClinVar classification: Benign (3 labs)Likely benign (2 labs)ClinVar ID 39179
Assessed · not applied
Pathogenic
PS1
No information available about a different nucleotide change at the same amino acid position (Thr1410) with an established pathogenic classification.
PS2
No confirmed de novo occurrence of NM_198578.3:c.4229C>T has been reported in the literature.
PS3
No well-established in vitro or in vivo functional studies demonstrate a damaging effect specific to the T1410M variant.
PS4
The variant is common in population databases, with allele frequencies inconsistent with a pathogenic role in Parkinson's disease.
PM1
While position 1410 is within the ROC/GTPase domain of LRRK2 and is the autophosphorylation site (PMID:21060682), the variant's high population frequency (AF >2% in African ancestry) and benign ClinVar classification are inconsistent with a pathogenic interpretation.
PM2
This variant is present in gnomAD at frequencies exceeding the PM2 threshold of <0.1%.
PM6
No confirmed de novo occurrence of this variant has been reported.
PP1
No segregation data are available for this variant.
PP2
LRRK2 has a high rate of benign missense variation in population databases; this variant itself is common (AF >2% in African ancestry).
PP3
Multiple in silico tools predict a benign effect: REVEL score 0.466 (below commonly used 0.5 damaging threshold), BayesDel score -0.172832 (below 0.13 damaging threshold), and SpliceAI max delta 0.15 (no predicted splice impact).
PP4
No detailed phenotype data specific to patients carrying this variant are available.
PP5
ClinVar classifies this variant as Benign (3 clinical laboratories) and Likely benign (2 clinical laboratories) (ClinVar variation ID 39179).
Benign
BS3
No well-established in vitro or in vivo functional studies demonstrate a benign effect specific to the T1410M variant.
BS4
No formal segregation data demonstrating lack of cosegregation with Parkinson's disease are available.
BP2
BP2 requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP5
No documentation available of this variant being found in a case with an alternative molecular basis for Parkinson's disease.
N/A · 7
PVS1 · PM3 · PM4 · PM5 · BP1 · BP3 · BP7
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