rs953836925
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_198578.4(LRRK2):āc.2818T>Gā(p.Phe940Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,540,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F940L) has been classified as Uncertain significance.
Frequency
Consequence
NM_198578.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRRK2 | NM_198578.4 | c.2818T>G | p.Phe940Val | missense_variant | 22/51 | ENST00000298910.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRRK2 | ENST00000298910.12 | c.2818T>G | p.Phe940Val | missense_variant | 22/51 | 1 | NM_198578.4 | P1 | |
LRRK2 | ENST00000680790.1 | c.2563T>G | p.Phe855Val | missense_variant | 20/49 | ||||
LRRK2 | ENST00000343742.6 | c.2818T>G | p.Phe940Val | missense_variant | 22/27 | 5 | |||
LRRK2 | ENST00000679360.1 | c.*1727T>G | 3_prime_UTR_variant, NMD_transcript_variant | 23/51 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152062Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248912Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134850
GnomAD4 exome AF: 0.0000130 AC: 18AN: 1388188Hom.: 0 Cov.: 24 AF XY: 0.0000159 AC XY: 11AN XY: 693570
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152062Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74288
ClinVar
Submissions by phenotype
Autosomal dominant Parkinson disease 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 577777). This variant has not been reported in the literature in individuals affected with LRRK2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 940 of the LRRK2 protein (p.Phe940Val). - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 15, 2024 | The p.F940V variant (also known as c.2818T>G), located in coding exon 22 of the LRRK2 gene, results from a T to G substitution at nucleotide position 2818. The phenylalanine at codon 940 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at