rs786204078
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The ENST00000375735.7(DYNC2H1):āc.3995T>Gā(p.Leu1332Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,308 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 Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
DYNC2H1
ENST00000375735.7 missense
ENST00000375735.7 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 7.70
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, 0.985
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYNC2H1 | NM_001080463.2 | c.3995T>G | p.Leu1332Arg | missense_variant | 26/90 | ENST00000650373.2 | NP_001073932.1 | |
DYNC2H1 | NM_001377.3 | c.3995T>G | p.Leu1332Arg | missense_variant | 26/89 | ENST00000375735.7 | NP_001368.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.3995T>G | p.Leu1332Arg | missense_variant | 26/90 | NM_001080463.2 | ENSP00000497174 | A1 | ||
DYNC2H1 | ENST00000375735.7 | c.3995T>G | p.Leu1332Arg | missense_variant | 26/89 | 1 | NM_001377.3 | ENSP00000364887 | P3 | |
DYNC2H1 | ENST00000334267.11 | c.2205+22219T>G | intron_variant | 1 | ENSP00000334021 | |||||
DYNC2H1 | ENST00000649323.1 | c.*1540T>G | 3_prime_UTR_variant, NMD_transcript_variant | 24/51 | ENSP00000497581 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461308Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726912
GnomAD4 exome
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2
AN:
1461308
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32
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0
AN XY:
726912
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Jeune thoracic dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 23, 2018 | This variant has not been reported in the literature in individuals with DYNC2H1-related disease. ClinVar contains an entry for this variant (Variation ID: 188115). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 1332 of the DYNC2H1 protein (p.Leu1332Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;D
REVEL
Pathogenic
Sift
Uncertain
D;.;.;D
Sift4G
Pathogenic
D;.;.;D
Polyphen
D;D;D;D
Vest4
MutPred
Gain of ubiquitination at K1331 (P = 0.0401);Gain of ubiquitination at K1331 (P = 0.0401);Gain of ubiquitination at K1331 (P = 0.0401);Gain of ubiquitination at K1331 (P = 0.0401);
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