rs758727391
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_001080463.2(DYNC2H1):āc.11291A>Gā(p.Gln3764Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,612,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 32)
Exomes š: 0.000044 ( 0 hom. )
Consequence
DYNC2H1
NM_001080463.2 missense
NM_001080463.2 missense
Scores
4
8
6
Clinical Significance
Conservation
PhyloP100: 9.18
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 Uncertain_significance. Variant got 3 ACMG points.
PM1
?
In a region_of_interest AAA 6 (size 215) in uniprot entity DYHC2_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001080463.2
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.3100356).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYNC2H1 | NM_001080463.2 | c.11291A>G | p.Gln3764Arg | missense_variant | 78/90 | ENST00000650373.2 | |
DYNC2H1 | NM_001377.3 | c.11270A>G | p.Gln3757Arg | missense_variant | 77/89 | ENST00000375735.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.11291A>G | p.Gln3764Arg | missense_variant | 78/90 | NM_001080463.2 | A1 | ||
DYNC2H1 | ENST00000375735.7 | c.11270A>G | p.Gln3757Arg | missense_variant | 77/89 | 1 | NM_001377.3 | P3 | |
DYNC2H1 | ENST00000334267.11 | c.2206-131335A>G | intron_variant | 1 | |||||
DYNC2H1 | ENST00000528670.5 | c.449A>G | p.Gln150Arg | missense_variant, NMD_transcript_variant | 5/17 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000218 AC: 54AN: 248048Hom.: 0 AF XY: 0.000178 AC XY: 24AN XY: 134574
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GnomAD4 exome AF: 0.0000438 AC: 64AN: 1460124Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29AN XY: 726350
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74326
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Jeune thoracic dystrophy Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2022 | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 3764 of the DYNC2H1 protein (p.Gln3764Arg). This variant is present in population databases (rs758727391, gnomAD 0.2%). This missense change has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446580). 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. 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. - |
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 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 25, 2023 | Variant summary: DYNC2H1 c.11291A>G (p.Gln3764Arg) results in a conservative amino acid change located in the Dynein heavy chain region D6 P-loop domain (IPR004273) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 248048 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia (0.00022 vs 0.0025), allowing no conclusion about variant significance. c.11291A>G has been reported in the literature in an individual diagnosed with asphyxiating thoracic dystrophy (ATD) (Zhang_2018); however, this report does not provide unequivocal conclusions about association of the variant with Short-rib thoracic dysplasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29068549). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: two classified the variant as uncertain significance, and one classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Asphyxiating thoracic dystrophy 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 11, 2021 | The DYNC2H1 c.11291A>G; p.Gln3764Arg variant (rs758727391) is published in the literature in a neonate with asphyxiating thoracic dystrophy who also carried another missense DYNCH2H1 variant on the opposite chromosome (Zhang 2018). The variant is reported in the ClinVar database (Variation ID: 446580) and is found in the Latino population with an allele frequency of 0.155% (53/34,282 alleles) in the Genome Aggregation Database. The glutamine at codon 3764 is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.555) Due to limited information, the clinical significance of the p.Gln3764Arg variant is uncertain at this time. References: Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. PMID: 29068549. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;D
REVEL
Uncertain
Sift
Uncertain
D;.;.;D
Sift4G
Uncertain
D;.;.;D
Polyphen
D;D;D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.1435);Gain of MoRF binding (P = 0.1435);.;.;
MVP
MPC
0.31
ClinPred
T
GERP RS
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Splicing
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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