rs141670992
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_004082.5(DCTN1):c.460C>T(p.Arg154Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000467 in 1,607,618 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R154H) has been classified as Uncertain significance.
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.460C>T | p.Arg154Cys | missense_variant | 8/32 | ENST00000628224.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DCTN1 | ENST00000628224.3 | c.460C>T | p.Arg154Cys | missense_variant | 8/32 | 5 | NM_004082.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000475 AC: 11AN: 231464Hom.: 0 AF XY: 0.0000396 AC XY: 5AN XY: 126160
GnomAD4 exome AF: 0.0000447 AC: 65AN: 1455498Hom.: 0 Cov.: 32 AF XY: 0.0000401 AC XY: 29AN XY: 723428
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74312
ClinVar
Submissions by phenotype
Neuronopathy, distal hereditary motor, type 7B;C1862939:Amyotrophic lateral sclerosis type 1;C1868594:Perry syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 154 of the DCTN1 protein (p.Arg154Cys). This variant is present in population databases (rs141670992, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DCTN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 574723). 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 expected to disrupt DCTN1 protein function with a positive predictive value of 80%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 11, 2022 | The p.R154C variant (also known as c.460C>T), located in coding exon 8 of the DCTN1 gene, results from a C to T substitution at nucleotide position 460. The arginine at codon 154 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at