rs755338872
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001080463.2(DYNC2H1):c.3353del(p.Ser1118IlefsTer46) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000498 in 1,566,604 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000054 ( 0 hom. )
Consequence
DYNC2H1
NM_001080463.2 frameshift
NM_001080463.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.88
Genes affected
DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-103154500-AG-A is Pathogenic according to our data. Variant chr11-103154500-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 195733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYNC2H1 | NM_001080463.2 | c.3353del | p.Ser1118IlefsTer46 | frameshift_variant | 23/90 | ENST00000650373.2 | |
DYNC2H1 | NM_001377.3 | c.3353del | p.Ser1118IlefsTer46 | frameshift_variant | 23/89 | ENST00000375735.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.3353del | p.Ser1118IlefsTer46 | frameshift_variant | 23/90 | NM_001080463.2 | A1 | ||
DYNC2H1 | ENST00000375735.7 | c.3353del | p.Ser1118IlefsTer46 | frameshift_variant | 23/89 | 1 | NM_001377.3 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152106Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000217 AC: 4AN: 184346Hom.: 0 AF XY: 0.0000407 AC XY: 4AN XY: 98348
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GnomAD4 exome AF: 0.0000544 AC: 77AN: 1414498Hom.: 0 Cov.: 31 AF XY: 0.0000501 AC XY: 35AN XY: 699260
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Jeune thoracic dystrophy Pathogenic:3
Pathogenic, no assertion criteria provided | research | Dan Cohn Lab, University Of California Los Angeles | Jun 01, 2017 | - - |
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change creates a premature translational stop signal (p.Ser1118Ilefs*46) 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). This variant is present in population databases (rs755338872, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with DYNC2H1-related conditions (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 195733). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 04, 2015 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at