chr14-101983222-A-G
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_001376.5(DYNC1H1):c.1165A>G(p.Ser389Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001376.5 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal dominant childhood-onset proximal spinal muscular atrophy without contracturesInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
- intellectual disability, autosomal dominant 13Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
- neuronopathy, distal hereditary motorInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- Charcot-Marie-Tooth disease axonal type 2OInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
- autosomal dominant non-syndromic intellectual disabilityInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152248Hom.: 0 Cov.: 31 show subpopulations
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461884Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727242 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152248Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74390 show subpopulations
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2O Uncertain:1
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 389 of the DYNC1H1 protein (p.Ser389Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DYNC1H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 539766). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DYNC1H1 protein function with a negative predictive value of 95%. 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. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25512093, 25609763, 26100331) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at