chr11-103199355-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 6P and 5B. PM1PM2PM5BP4_StrongBP6

The NM_001080463.2(DYNC2H1):​c.7967G>A​(p.Arg2656His) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,612,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2656C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

3
9
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:1

Conservation

PhyloP100: 4.82

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: Uncertain_significance. The variant received 1 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001080463.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-103199354-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 446533.
BP4
Computational evidence support a benign effect (MetaRNN=0.01862505).
BP6
Variant 11-103199355-G-A is Benign according to our data. Variant chr11-103199355-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 446620. Variant chr11-103199355-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 446620. Variant chr11-103199355-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 446620. Variant chr11-103199355-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 446620. Variant chr11-103199355-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 446620. Variant chr11-103199355-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 446620.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DYNC2H1NM_001080463.2 linkc.7967G>A p.Arg2656His missense_variant Exon 49 of 90 ENST00000650373.2 NP_001073932.1 Q8NCM8-2
DYNC2H1NM_001377.3 linkc.7967G>A p.Arg2656His missense_variant Exon 49 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.7967G>A p.Arg2656His missense_variant Exon 49 of 90 NM_001080463.2 ENSP00000497174.1 Q8NCM8-2
DYNC2H1ENST00000375735.7 linkc.7967G>A p.Arg2656His missense_variant Exon 49 of 89 1 NM_001377.3 ENSP00000364887.2 Q8NCM8-1

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152096
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00634
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000290
AC:
72
AN:
248566
AF XY:
0.000245
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000580
Gnomad ASJ exome
AF:
0.00587
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.0000622
Gnomad OTH exome
AF:
0.000332
GnomAD4 exome
AF:
0.000138
AC:
201
AN:
1460158
Hom.:
0
Cov.:
31
AF XY:
0.000140
AC XY:
102
AN XY:
726368
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33420
American (AMR)
AF:
0.0000671
AC:
3
AN:
44702
Ashkenazi Jewish (ASJ)
AF:
0.00509
AC:
133
AN:
26122
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39630
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86190
European-Finnish (FIN)
AF:
0.0000375
AC:
2
AN:
53382
Middle Eastern (MID)
AF:
0.000418
AC:
2
AN:
4788
European-Non Finnish (NFE)
AF:
0.0000405
AC:
45
AN:
1111672
Other (OTH)
AF:
0.000249
AC:
15
AN:
60252
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
12
24
35
47
59
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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
AF:
0.000171
AC:
26
AN:
152096
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74300
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41418
American (AMR)
AF:
0.00
AC:
0
AN:
15266
Ashkenazi Jewish (ASJ)
AF:
0.00634
AC:
22
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10596
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
68008
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.490
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.000258
Hom.:
0
Bravo
AF:
0.000170
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000242
AC:
2
ExAC
AF:
0.000265
AC:
32
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:2Benign:1
-
University of Washington Center for Mendelian Genomics, University of Washington
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
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

- -

not provided Uncertain:1
Nov 09, 2020
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Identified in a prenatal proband with short-rib polydactyly syndromes in published literature (Zhang et al., 2018); 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: 29068549, 31589614, 33369054) -

Asphyxiating thoracic dystrophy 3 Uncertain:1
Jan 06, 2020
Reproductive Health Research and Development, BGI Genomics
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:curation

NM_001080463.1:c.7967G>A in the DYNC2H1 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster and SIFT. Zhang et al reported a Caucasian patient with short-rib polydactyly syndromes type I (c.[7268C>A];[7967G>T], in trans) and a Latino patient with asphyxiating thoracic dystrophy ([5984C>T];[7967G>T], in trans)(PMID: 29068549). However, the pathogenicity of c.7268C>A and 5984C>T was uncertain. We interpret it as a variant of uncertain significance favor of likely pathogenic. ACMG/AMP criteria applied: PP3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.34
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.58
D;D;.;.
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
.;D;.;D
M_CAP
Benign
0.032
D
MetaRNN
Benign
0.019
T;T;T;T
MetaSVM
Benign
-0.63
T
MutationAssessor
Uncertain
2.6
M;M;M;M
PhyloP100
4.8
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-4.2
D;.;.;D
REVEL
Uncertain
0.30
Sift
Uncertain
0.025
D;.;.;D
Sift4G
Uncertain
0.031
D;.;.;D
Polyphen
0.91
P;P;D;D
Vest4
0.36
MVP
0.69
MPC
0.19
ClinPred
0.24
T
GERP RS
6.1
Varity_R
0.63
gMVP
0.65
Mutation Taster
=13/87
disease causing

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

Other links and lift over

dbSNP: rs200614421; hg19: chr11-103070084; API