rs780600124
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_001080463.2(DYNC2H1):c.9865G>A(p.Asp3289Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D3289A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001080463.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYNC2H1 | NM_001080463.2 | c.9865G>A | p.Asp3289Asn | missense_variant | 65/90 | ENST00000650373.2 | |
DYNC2H1 | NM_001377.3 | c.9844G>A | p.Asp3282Asn | missense_variant | 64/89 | ENST00000375735.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.9865G>A | p.Asp3289Asn | missense_variant | 65/90 | NM_001080463.2 | A1 | ||
DYNC2H1 | ENST00000375735.7 | c.9844G>A | p.Asp3282Asn | missense_variant | 64/89 | 1 | NM_001377.3 | P3 | |
DYNC2H1 | ENST00000334267.11 | c.2205+109298G>A | intron_variant | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000840 AC: 2AN: 238026Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 128624
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1453176Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 722060
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jan 05, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
Asphyxiating thoracic dystrophy 3 Pathogenic:2
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Pathogenic, no assertion criteria provided | research | Dan Cohn Lab, University Of California Los Angeles | Jun 01, 2017 | - - |
Jeune thoracic dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 10, 2023 | 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 DYNC2H1 protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 446534). This missense change has been observed in individual(s) with clinical features of short-rib polydactyly syndrome (PMID: 29068549; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs780600124, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 3289 of the DYNC2H1 protein (p.Asp3289Asn). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at