rs1555082470

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001377.3(DYNC2H1):​c.10603C>T​(p.Gln3535*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

DYNC2H1
NM_001377.3 stop_gained, splice_region

Scores

4
2
1
Splicing: ADA: 0.8300
2

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 3.06
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 11 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 11-103257749-C-T is Pathogenic according to our data. Variant chr11-103257749-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446581.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DYNC2H1NM_001080463.2 linkc.10624C>T p.Gln3542* stop_gained, splice_region_variant 70/90 ENST00000650373.2 NP_001073932.1 Q8NCM8-2
DYNC2H1NM_001377.3 linkc.10603C>T p.Gln3535* stop_gained, splice_region_variant 69/89 ENST00000375735.7 NP_001368.2 Q8NCM8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DYNC2H1ENST00000650373.2 linkc.10624C>T p.Gln3542* stop_gained, splice_region_variant 70/90 NM_001080463.2 ENSP00000497174.1 Q8NCM8-2
DYNC2H1ENST00000375735.7 linkc.10603C>T p.Gln3535* stop_gained, splice_region_variant 69/891 NM_001377.3 ENSP00000364887.2 Q8NCM8-1
DYNC2H1ENST00000334267.11 linkc.2205+123330C>T intron_variant 1 ENSP00000334021.7 Q8NCM8-3
ENSG00000285878ENST00000649070.1 linkn.691-5445G>A intron_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
6.97e-7
AC:
1
AN:
1434056
Hom.:
0
Cov.:
30
AF XY:
0.00000141
AC XY:
1
AN XY:
710936
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.11e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Pathogenic:2
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -
Pathogenic, no assertion criteria providedresearchDan Cohn Lab, University Of California Los AngelesJun 01, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
50
DANN
Uncertain
1.0
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.92
D
Vest4
0.88
GERP RS
5.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.83
dbscSNV1_RF
Benign
0.57
SpliceAI score (max)
0.0
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: rs1555082470; hg19: chr11-103128478; API