NM_001080463.2:c.9565C>T
Variant summary
Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1PM2PP3_ModeratePP5_Moderate
The NM_001080463.2(DYNC2H1):c.9565C>T(p.Gln3189*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000694 in 1,584,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001080463.2 stop_gained, splice_region
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 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYNC2H1 | NM_001080463.2 | c.9565C>T | p.Gln3189* | stop_gained, splice_region_variant | Exon 61 of 90 | ENST00000650373.2 | NP_001073932.1 | |
DYNC2H1 | NM_001377.3 | c.9565C>T | p.Gln3189* | stop_gained, splice_region_variant | Exon 61 of 89 | ENST00000375735.7 | NP_001368.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.9565C>T | p.Gln3189* | stop_gained, splice_region_variant | Exon 61 of 90 | NM_001080463.2 | ENSP00000497174.1 | |||
DYNC2H1 | ENST00000375735.7 | c.9565C>T | p.Gln3189* | stop_gained, splice_region_variant | Exon 61 of 89 | 1 | NM_001377.3 | ENSP00000364887.2 | ||
DYNC2H1 | ENST00000334267.11 | c.2205+99739C>T | intron_variant | Intron 15 of 19 | 1 | ENSP00000334021.7 |
Frequencies
GnomAD3 genomes AF: 0.0000264 AC: 4AN: 151718Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.00000965 AC: 2AN: 207268 AF XY: 0.00000904 show subpopulations
GnomAD4 exome AF: 0.00000489 AC: 7AN: 1432422Hom.: 0 Cov.: 31 AF XY: 0.00000705 AC XY: 5AN XY: 709522 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000264 AC: 4AN: 151718Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2AN XY: 74072 show subpopulations
ClinVar
Submissions by phenotype
Asphyxiating thoracic dystrophy 3 Pathogenic:2
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Jeune thoracic dystrophy Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gln3189*) in the DYNC2H1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYNC2H1 are known to be pathogenic (PMID: 23339108, 32753734, 33755199). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of DYNC2H1-related conditions (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446542). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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