rs745870321

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_001080463.2(DYNC2H1):​c.4267C>T​(p.Arg1423Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,452,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1423H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

17
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.56

Publications

4 publications found
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]
DYNC2H1 Gene-Disease associations (from GenCC):
  • asphyxiating thoracic dystrophy 3
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
  • Jeune syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • short rib-polydactyly syndrome, Majewski type
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • short rib-polydactyly syndrome, Verma-Naumoff type
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-103158917-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2573452.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
Variant 11-103158916-C-T is Pathogenic according to our data. Variant chr11-103158916-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DYNC2H1NM_001080463.2 linkc.4267C>T p.Arg1423Cys missense_variant Exon 28 of 90 ENST00000650373.2 NP_001073932.1 Q8NCM8-2
DYNC2H1NM_001377.3 linkc.4267C>T p.Arg1423Cys missense_variant Exon 28 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.4267C>T p.Arg1423Cys missense_variant Exon 28 of 90 NM_001080463.2 ENSP00000497174.1 Q8NCM8-2
DYNC2H1ENST00000375735.7 linkc.4267C>T p.Arg1423Cys missense_variant Exon 28 of 89 1 NM_001377.3 ENSP00000364887.2 Q8NCM8-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000291
AC:
7
AN:
240168
AF XY:
0.0000385
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000172
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000183
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1452986
Hom.:
0
Cov.:
31
AF XY:
0.0000194
AC XY:
14
AN XY:
721730
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33156
American (AMR)
AF:
0.0000230
AC:
1
AN:
43512
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25930
East Asian (EAS)
AF:
0.0000760
AC:
3
AN:
39498
South Asian (SAS)
AF:
0.0000242
AC:
2
AN:
82688
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53244
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5756
European-Non Finnish (NFE)
AF:
0.0000135
AC:
15
AN:
1109060
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60142
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.477
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000610
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Pathogenic:6
Dec 07, 2016
University of Washington Center for Mendelian Genomics, University of Washington
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

Feb 26, 2020
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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

- -

-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PM2_Supporting+PP3_Strong+PM3_VeryStrong -

Feb 28, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 14, 2021
Genomic Medicine Lab, University of California San Francisco
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Pathogenic:1
May 21, 2024
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27925158, 29458881, 34675960, 29068549, 35627109, 22499340) -

Jeune thoracic dystrophy Pathogenic:1
Feb 08, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1423 of the DYNC2H1 protein (p.Arg1423Cys). This variant is present in population databases (rs745870321, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of short-rib polydactyly syndrome (PMID: 22499340, 27925158, 29068549). ClinVar contains an entry for this variant (Variation ID: 446611). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.87
D;D;.;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
.;D;.;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Pathogenic
4.6
H;H;H;H
PhyloP100
7.6
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-7.4
D;.;.;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;.;.;D
Sift4G
Pathogenic
0.0
D;.;.;D
Polyphen
1.0
D;D;D;D
Vest4
0.98
MutPred
0.90
Loss of disorder (P = 0.0222);Loss of disorder (P = 0.0222);Loss of disorder (P = 0.0222);Loss of disorder (P = 0.0222);
MVP
0.87
MPC
0.44
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.88
gMVP
0.87
Mutation Taster
=2/98
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs745870321; hg19: chr11-103029645; COSMIC: COSV62095418; API