rs1555053115
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The ENST00000375735.7(DYNC2H1):c.4553G>A(p.Cys1518Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
Consequence
DYNC2H1
ENST00000375735.7 missense
ENST00000375735.7 missense
Scores
9
6
4
Clinical Significance
Conservation
PhyloP100: 8.41
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.939
PP5
Variant 11-103163089-G-A is Pathogenic according to our data. Variant chr11-103163089-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446596.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYNC2H1 | NM_001080463.2 | c.4553G>A | p.Cys1518Tyr | missense_variant | 30/90 | ENST00000650373.2 | NP_001073932.1 | |
DYNC2H1 | NM_001377.3 | c.4553G>A | p.Cys1518Tyr | missense_variant | 30/89 | ENST00000375735.7 | NP_001368.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.4553G>A | p.Cys1518Tyr | missense_variant | 30/90 | NM_001080463.2 | ENSP00000497174 | A1 | ||
DYNC2H1 | ENST00000375735.7 | c.4553G>A | p.Cys1518Tyr | missense_variant | 30/89 | 1 | NM_001377.3 | ENSP00000364887 | P3 | |
DYNC2H1 | ENST00000334267.11 | c.2205+28670G>A | intron_variant | 1 | ENSP00000334021 | |||||
DYNC2H1 | ENST00000649323.1 | c.*2098G>A | 3_prime_UTR_variant, NMD_transcript_variant | 28/51 | ENSP00000497581 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Bravo
AF:
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Jeune thoracic dystrophy Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 28, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 446596). This missense change has been observed in individual(s) with DYNC2H1-related conditions (PMID: 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1518 of the DYNC2H1 protein (p.Cys1518Tyr). - |
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 | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;T;.;T
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;D
REVEL
Uncertain
Sift
Pathogenic
D;.;.;D
Sift4G
Benign
T;.;.;T
Polyphen
D;D;D;D
Vest4
MutPred
Loss of catalytic residue at T1520 (P = 0.1218);Loss of catalytic residue at T1520 (P = 0.1218);Loss of catalytic residue at T1520 (P = 0.1218);Loss of catalytic residue at T1520 (P = 0.1218);
MVP
MPC
0.45
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