rs121909345
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_004082.5(DCTN1):c.3302G>A(p.Arg1101Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,272 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R1101R) has been classified as Likely benign.
Frequency
Consequence
NM_004082.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DCTN1 | NM_004082.5 | c.3302G>A | p.Arg1101Lys | missense_variant | 28/32 | ENST00000628224.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DCTN1 | ENST00000628224.3 | c.3302G>A | p.Arg1101Lys | missense_variant | 28/32 | 5 | NM_004082.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249326Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134758
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461090Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 726730
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 03, 2021 | The p.R1101K variant (also known as c.3302G>A), located in coding exon 28 of the DCTN1 gene, results from a G to A substitution at nucleotide position 3302. The arginine at codon 1101 is replaced by lysine, an amino acid with highly similar properties. This variant was identified in the heterozygous state in a pair of siblings, one of whom had amyotrophic lateral sclerosis (ALS) and one of whom had frontotemporal dementia (FTD) (Münch C et al. Ann Neurol, 2005 Nov;58:777-80). In vitro experimental studies show that this alteration does not significantly impact protein function (Dixit R et al. J Biol Chem, 2008 Nov;283:33611-9; Stockmann M et al. J Neural Transm (Vienna), 2013 May;120:785-98). This amino acid position is well conserved in available vertebrate species; however, lysine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Neuronopathy, distal hereditary motor, type 7B;C1862939:Amyotrophic lateral sclerosis type 1;C1868594:Perry syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1101 of the DCTN1 protein (p.Arg1101Lys). This variant is present in population databases (rs121909345, gnomAD 0.006%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis and frontotemporal dementia (PMID: 16240349). ClinVar contains an entry for this variant (Variation ID: 8405). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DCTN1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect DCTN1 function (PMID: 18812314, 23143281). 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. - |
Perry syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Amyotrophic lateral sclerosis, susceptibility to Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Nov 01, 2005 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at