rs1555053115

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The ENST00000375735.7(DYNC2H1):​c.4553G>A​(p.Cys1518Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

DYNC2H1
ENST00000375735.7 missense

Scores

9
6
4

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 8.41
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.939
PP5
Variant 11-103163089-G-A is Pathogenic according to our data. Variant chr11-103163089-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446596.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DYNC2H1NM_001080463.2 linkuse as main transcriptc.4553G>A p.Cys1518Tyr missense_variant 30/90 ENST00000650373.2 NP_001073932.1
DYNC2H1NM_001377.3 linkuse as main transcriptc.4553G>A p.Cys1518Tyr missense_variant 30/89 ENST00000375735.7 NP_001368.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DYNC2H1ENST00000650373.2 linkuse as main transcriptc.4553G>A p.Cys1518Tyr missense_variant 30/90 NM_001080463.2 ENSP00000497174 A1Q8NCM8-2
DYNC2H1ENST00000375735.7 linkuse as main transcriptc.4553G>A p.Cys1518Tyr missense_variant 30/891 NM_001377.3 ENSP00000364887 P3Q8NCM8-1
DYNC2H1ENST00000334267.11 linkuse as main transcriptc.2205+28670G>A intron_variant 1 ENSP00000334021 Q8NCM8-3
DYNC2H1ENST00000649323.1 linkuse as main transcriptc.*2098G>A 3_prime_UTR_variant, NMD_transcript_variant 28/51 ENSP00000497581

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 28, 2022In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYNC2H1 protein function. ClinVar contains an entry for this variant (Variation ID: 446596). This missense change has been observed in individual(s) with DYNC2H1-related conditions (PMID: 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1518 of the DYNC2H1 protein (p.Cys1518Tyr). -
Pathogenic, no assertion criteria providedresearchDan Cohn Lab, University Of California Los AngelesJun 01, 2017- -
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;D;.;.
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.83
.;T;.;T
M_CAP
Benign
0.064
D
MetaRNN
Pathogenic
0.94
D;D;D;D
MetaSVM
Uncertain
-0.083
T
MutationAssessor
Uncertain
2.5
M;M;M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-8.3
D;.;.;D
REVEL
Uncertain
0.63
Sift
Pathogenic
0.0
D;.;.;D
Sift4G
Benign
0.082
T;.;.;T
Polyphen
0.99
D;D;D;D
Vest4
0.92
MutPred
0.77
Loss of catalytic residue at T1520 (P = 0.1218);Loss of catalytic residue at T1520 (P = 0.1218);Loss of catalytic residue at T1520 (P = 0.1218);Loss of catalytic residue at T1520 (P = 0.1218);
MVP
0.75
MPC
0.45
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.97
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
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: rs1555053115; hg19: chr11-103033818; API