rs1453448143

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001377.3(DYNC2H1):​c.11713_11716delAGAC​(p.Arg3905PhefsTer26) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

DYNC2H1
NM_001377.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 9.36
Variant links:
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 Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-103316604-TGACA-T is Pathogenic according to our data. Variant chr11-103316604-TGACA-T is described in ClinVar as [Pathogenic]. Clinvar id is 446583.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DYNC2H1NM_001080463.2 linkc.11734_11737delAGAC p.Arg3912PhefsTer26 frameshift_variant Exon 81 of 90 ENST00000650373.2 NP_001073932.1 Q8NCM8-2
DYNC2H1NM_001377.3 linkc.11713_11716delAGAC p.Arg3905PhefsTer26 frameshift_variant Exon 80 of 89 ENST00000375735.7 NP_001368.2 Q8NCM8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DYNC2H1ENST00000650373.2 linkc.11734_11737delAGAC p.Arg3912PhefsTer26 frameshift_variant Exon 81 of 90 NM_001080463.2 ENSP00000497174.1 Q8NCM8-2
DYNC2H1ENST00000375735.7 linkc.11713_11716delAGAC p.Arg3905PhefsTer26 frameshift_variant Exon 80 of 89 1 NM_001377.3 ENSP00000364887.2 Q8NCM8-1
DYNC2H1ENST00000334267.11 linkc.2206-119335_2206-119332delAGAC intron_variant Intron 15 of 19 1 ENSP00000334021.7 Q8NCM8-3
DYNC2H1ENST00000528670.5 linkn.892_895delAGAC non_coding_transcript_exon_variant Exon 8 of 17 5 ENSP00000433451.1 H0YDE0

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Pathogenic:2
Jun 01, 2017
Dan Cohn Lab, University Of California Los Angeles
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

-
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Jeune thoracic dystrophy Pathogenic:1
Dec 01, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg3912Phefs*26) in the DYNC2H1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYNC2H1 are known to be pathogenic (PMID: 23339108, 32753734, 33755199). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with DYNC2H1-related conditions (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446583). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1453448143; hg19: chr11-103187333; API