rs745870321
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_001080463.2(DYNC2H1):c.4267C>T(p.Arg1423Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,452,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. R1423H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001080463.2 missense
Scores
Clinical Significance
Conservation
Publications
- asphyxiating thoracic dystrophy 3Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
- Jeune syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- short rib-polydactyly syndrome, Majewski typeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- short rib-polydactyly syndrome, Verma-Naumoff typeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYNC2H1 | NM_001080463.2 | c.4267C>T | p.Arg1423Cys | missense_variant | Exon 28 of 90 | ENST00000650373.2 | NP_001073932.1 | |
DYNC2H1 | NM_001377.3 | c.4267C>T | p.Arg1423Cys | missense_variant | Exon 28 of 89 | ENST00000375735.7 | NP_001368.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.4267C>T | p.Arg1423Cys | missense_variant | Exon 28 of 90 | NM_001080463.2 | ENSP00000497174.1 | |||
DYNC2H1 | ENST00000375735.7 | c.4267C>T | p.Arg1423Cys | missense_variant | Exon 28 of 89 | 1 | NM_001377.3 | ENSP00000364887.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.0000291 AC: 7AN: 240168 AF XY: 0.0000385 show subpopulations
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1452986Hom.: 0 Cov.: 31 AF XY: 0.0000194 AC XY: 14AN XY: 721730 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Asphyxiating thoracic dystrophy 3 Pathogenic:6
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PM2_Supporting+PP3_Strong+PM3_VeryStrong -
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not provided Pathogenic:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27925158, 29458881, 34675960, 29068549, 35627109, 22499340) -
Jeune thoracic dystrophy Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1423 of the DYNC2H1 protein (p.Arg1423Cys). This variant is present in population databases (rs745870321, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of short-rib polydactyly syndrome (PMID: 22499340, 27925158, 29068549). ClinVar contains an entry for this variant (Variation ID: 446611). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at