rs137853031
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_001377.3(DYNC2H1):c.6614G>A(p.Arg2205His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 1,457,144 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 (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
DYNC2H1
NM_001377.3 missense
NM_001377.3 missense
Scores
4
11
4
Clinical Significance
Conservation
PhyloP100: 9.55
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 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.751
PP5
Variant 11-103185032-G-A is Pathogenic according to our data. Variant chr11-103185032-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.6614G>A | p.Arg2205His | missense_variant | 41/90 | NM_001080463.2 | ENSP00000497174.1 | |||
DYNC2H1 | ENST00000375735.7 | c.6614G>A | p.Arg2205His | missense_variant | 41/89 | 1 | NM_001377.3 | ENSP00000364887.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247320Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134234
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GnomAD4 exome AF: 0.00000892 AC: 13AN: 1457144Hom.: 0 Cov.: 30 AF XY: 0.00000966 AC XY: 7AN XY: 724822
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Asphyxiating thoracic dystrophy 3 Pathogenic:4
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 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2009 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Oct 04, 2022 | The DYNC2H1 c.6614G>A variant is classified as Likely Pathogenic (PS4_Moderate, PM2, PM3) The DYNC2H1 c.6614G>A variant is a single nucleotide change in exon 41 of 89 of the DYNC2H1 gene, which is predicted to change the amino acid arginine at position 2205 in the protein to histidine. The variant has been reported in at least 2 probands with a clinical presentation of short rib-polydactyly syndrome (PMID:19361615, PMID:29068549) (PS4_Moderate). This variant is absent from population databases (PM2). The phase of this variant with the p.Trp860Ter variant cannot be determined without parental studies. However, this variant was reported to be in trans with a pathogenic variant p.Arg2838Ter for this recessive condition (PMID:19361615) (PM3). Computational predictions provide conflicting interpretations of pathogenicity for this variant (PP3 and BP4 not met). The variant has been reported in dbSNP (rs137853031) and in the HGMD database: CM091950. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 6507). - |
Jeune thoracic dystrophy Pathogenic:3
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2205 of the DYNC2H1 protein (p.Arg2205His). This variant is present in population databases (rs137853031, gnomAD 0.003%). This missense change has been observed in individual(s) with short rib polydactyly syndrome (PMID: 19361615, 29068549). 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: 6507). 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. - |
Pathogenic, no assertion criteria provided | research | Dan Cohn Lab, University Of California Los Angeles | Jun 01, 2017 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 30, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
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
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;D
REVEL
Uncertain
Sift
Uncertain
D;.;.;D
Sift4G
Uncertain
D;.;.;D
Polyphen
P;P;D;D
Vest4
MVP
MPC
0.41
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at