rs552436294
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong
The NM_001377.3(DYNC2H1):c.5983G>A(p.Ala1995Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000384 in 1,613,374 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A1995V) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000030 ( 0 hom. )
Consequence
DYNC2H1
NM_001377.3 missense
NM_001377.3 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 6.61
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 14 ACMG points.
PM1
In a region_of_interest AAA 2 (size 223) in uniprot entity DYHC2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001377.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-103177665-C-T is described in Lovd as [Pathogenic].
PP5
Variant 11-103177664-G-A is Pathogenic according to our data. Variant chr11-103177664-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 419236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYNC2H1 | NM_001080463.2 | c.5983G>A | p.Ala1995Thr | missense_variant | 38/90 | ENST00000650373.2 | NP_001073932.1 | |
DYNC2H1 | NM_001377.3 | c.5983G>A | p.Ala1995Thr | missense_variant | 38/89 | ENST00000375735.7 | NP_001368.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.5983G>A | p.Ala1995Thr | missense_variant | 38/90 | NM_001080463.2 | ENSP00000497174.1 | |||
DYNC2H1 | ENST00000375735.7 | c.5983G>A | p.Ala1995Thr | missense_variant | 38/89 | 1 | NM_001377.3 | ENSP00000364887.2 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152074Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248298Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134706
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GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461184Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 726856
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GnomAD4 genome AF: 0.000118 AC: 18AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74390
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Jeune thoracic dystrophy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1995 of the DYNC2H1 protein (p.Ala1995Thr). This variant is present in population databases (rs552436294, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of short-rib polydactyly syndrome (PMID: 29068549, 32494556). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 419236). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYNC2H1 protein function. For these reasons, this variant has been classified as Pathogenic. - |
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 | - | - - |
Asphyxiating thoracic dystrophy 3 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 21, 2022 | - - |
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 | - | - - |
DYNC2H1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 06, 2023 | The DYNC2H1 c.5983G>A variant is predicted to result in the amino acid substitution p.Ala1995Thr. This variant was reported in at least four unrelated cases of short rib-polydactyly syndrome, type 3 (Table S2, Zhang et al. 2018. PubMed ID: 29068549; Geng et al. 2020. PubMed ID: 32494556). A different substitution affecting the same amino acid (p.Ala1995Val) was also reported in patients with short rib-polydactyly syndrome (Table S2, Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.0088% of alleles in individuals of Latino descent in gnomAD. At PreventionGenetics, we have observed this variant in an individual tested for short rib skeletal dysplasia. This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 27, 2023 | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31589614, 29068549, 32494556) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;.;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L;L
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;D
REVEL
Benign
Sift
Uncertain
D;.;.;D
Sift4G
Uncertain
D;.;.;D
Polyphen
P;P;P;P
Vest4
MutPred
Gain of phosphorylation at A1995 (P = 0.0783);Gain of phosphorylation at A1995 (P = 0.0783);Gain of phosphorylation at A1995 (P = 0.0783);Gain of phosphorylation at A1995 (P = 0.0783);
MVP
MPC
0.25
ClinPred
D
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at