chr2-74376741-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_ModeratePP3_ModerateBS2
The NM_004082.5(DCTN1):c.414+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000623 in 1,604,832 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004082.5 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DCTN1 | NM_004082.5 | c.414+1G>A | splice_donor_variant | ENST00000628224.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DCTN1 | ENST00000628224.3 | c.414+1G>A | splice_donor_variant | 5 | NM_004082.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152232Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000635 AC: 15AN: 236150Hom.: 0 AF XY: 0.0000473 AC XY: 6AN XY: 126892
GnomAD4 exome AF: 0.0000613 AC: 89AN: 1452600Hom.: 1 Cov.: 30 AF XY: 0.0000568 AC XY: 41AN XY: 721322
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74372
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 | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 25, 2023 | 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. ClinVar contains an entry for this variant (Variation ID: 282607). Disruption of this splice site has been observed in individual(s) with clinical features of distal hereditary motor neuropathy (PMID: 33369814). This variant is present in population databases (rs576198476, gnomAD 0.03%). This sequence change affects a donor splice site in intron 5 of the DCTN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in DCTN1 cause disease. - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 05, 2019 | ACMG classification criteria: PVS1, PM2, PP3 - |
DCTN1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The DCTN1 c.414+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.00004 in the Total population from the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for DCTN1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 13, 2015 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 22, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at