chr11-103116688-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001080463.2(DYNC2H1):c.740G>A(p.Arg247Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000873 in 1,602,814 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 (★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
DYNC2H1
NM_001080463.2 missense
NM_001080463.2 missense
Scores
8
4
1
Clinical Significance
Conservation
PhyloP100: 9.60
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.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.825
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYNC2H1 | NM_001080463.2 | c.740G>A | p.Arg247Gln | missense_variant | 5/90 | ENST00000650373.2 | |
DYNC2H1 | NM_001377.3 | c.740G>A | p.Arg247Gln | missense_variant | 5/89 | ENST00000375735.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.740G>A | p.Arg247Gln | missense_variant | 5/90 | NM_001080463.2 | A1 | ||
DYNC2H1 | ENST00000375735.7 | c.740G>A | p.Arg247Gln | missense_variant | 5/89 | 1 | NM_001377.3 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152064Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000123 AC: 3AN: 243188Hom.: 0 AF XY: 0.0000227 AC XY: 3AN XY: 132132
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GnomAD4 exome AF: 0.00000551 AC: 8AN: 1450750Hom.: 0 Cov.: 30 AF XY: 0.00000831 AC XY: 6AN XY: 721620
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GnomAD4 genome AF: 0.0000395 AC: 6AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74270
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Asphyxiating thoracic dystrophy 3 Pathogenic:1Uncertain:1
Uncertain significance, 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 | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 03, 2023 | Variant summary: DYNC2H1 c.740G>A (p.Arg247Gln) results in a conservative amino acid change located in the Dynein heavy chain, tail (IPR013594) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 243188 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.740G>A has been reported in the literature in a heterozygous individual affected with Short-rib polydactyly syndrome type 3 without a second variant identified (Zhang_2018). 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). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D;.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Polyphen
0.98, 1.0, 1.0
.;D;D;D;D;D
Vest4
0.94, 0.98, 0.94
MVP
0.77
MPC
0.40
ClinPred
D
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