rs878854167
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001080463.2(DYNC2H1):c.7495C>G(p.Leu2499Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
DYNC2H1
NM_001080463.2 missense
NM_001080463.2 missense
Scores
2
6
10
Clinical Significance
Conservation
PhyloP100: 4.92
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 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYNC2H1 | NM_001080463.2 | c.7495C>G | p.Leu2499Val | missense_variant | 46/90 | ENST00000650373.2 | |
DYNC2H1 | NM_001377.3 | c.7495C>G | p.Leu2499Val | missense_variant | 46/89 | ENST00000375735.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.7495C>G | p.Leu2499Val | missense_variant | 46/90 | NM_001080463.2 | A1 | ||
DYNC2H1 | ENST00000375735.7 | c.7495C>G | p.Leu2499Val | missense_variant | 46/89 | 1 | NM_001377.3 | P3 | |
DYNC2H1 | ENST00000334267.11 | c.2205+57155C>G | intron_variant | 1 | |||||
DYNC2H1 | ENST00000649323.1 | c.*5040C>G | 3_prime_UTR_variant, NMD_transcript_variant | 44/51 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
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 | Invitae | May 10, 2018 | This sequence change replaces leucine with valine at codon 2499 of the DYNC2H1 protein (p.Leu2499Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with asphyxiating thoracic dysplasia (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 238274). 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
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;N
REVEL
Benign
Sift
Benign
T;.;.;T
Sift4G
Uncertain
T;.;.;T
Polyphen
P;P;P;P
Vest4
MutPred
Gain of catalytic residue at L2499 (P = 0.0438);Gain of catalytic residue at L2499 (P = 0.0438);Gain of catalytic residue at L2499 (P = 0.0438);Gain of catalytic residue at L2499 (P = 0.0438);
MVP
MPC
0.22
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