rs759549373

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM5PP3PP5

The NM_001080463.2(DYNC2H1):c.10121G>A(p.Arg3374His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,612,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R3374C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3B:1

Conservation

PhyloP100: 9.99

Publications

5 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

DYNC2H1 links:

ENSG00000285878 (HGNC:):

ENSG00000285878 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a strand (size 5) in uniprot entity DYHC2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001080463.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-103253341-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.818

PP5

Variant 11-103253342-G-A is Pathogenic according to our data. Variant chr11-103253342-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 369660.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.10121G>A	p.Arg3374His	missense_variant	Exon 67 of 90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 link	c.10100G>A	p.Arg3367His	missense_variant	Exon 66 of 89	ENST00000375735.7	NP_001368.2	Q8NCM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DYNC2H1	ENST00000650373.2 link	c.10121G>A	p.Arg3374His	missense_variant	Exon 67 of 90		NM_001080463.2	ENSP00000497174.1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 link	c.10100G>A	p.Arg3367His	missense_variant	Exon 66 of 89	1	NM_001377.3	ENSP00000364887.2	Q8NCM8-1
DYNC2H1	ENST00000334267.11 link	c.2205+118923G>A		intron_variant	Intron 15 of 19	1		ENSP00000334021.7	Q8NCM8-3
ENSG00000285878	ENST00000649070.1 link	n.691-1038C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000603

AC:

AN:

248894

AF XY:

0.0000741

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461024

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

726776

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33452

American (AMR)

AF:

0.000224

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000306

AC:

AN:

1111460

Other (OTH)

AF:

0.0000166

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74196

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41380

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67970

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000414

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 3

Pathogenic:1Uncertain:1

Jul 11, 2014

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This substitution is predicted to create a change of an arginine to a histidine at amino acid position 3374, NP_001073932.1(DYNC2H1): p.Arg3374His). The arginine at this position is highly conserved and is located in the ATP-binding dynein motor region D5. In-silico software predicts this variant to be disease-causing. this is a novel variant not present in disease or population databases. It was identified in a patient with clinical and radiographic features of JATD, and a second novel missense variant in the DYNC2H1 gene was present in trans. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PM3+PP4 -

DYNC2H1-related disorder

Pathogenic:1

Sep 19, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DYNC2H1 c.10121G>A variant is predicted to result in the amino acid substitution p.Arg3374His. This variant was observed in the confirmed compound heterozygous state in a patient with short ribs, bell-shaped chest, and skeletal dysplasia (Supplementary Table 1, Dillon et al. 2018. PubMed ID: 29453417). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD. In addition, another missense variant at the same residue resulting in a different amino acid change, p.Arg3374Cys, was reported along with a second pathogenic variant in a patient with asphyxiating thoracic dystrophy (Table S2, Zhang et al. 2018. PubMed ID: 29068549). Taken together, the c.10121G>A (p.Arg3374His) variant is interpreted as likely pathogenic. -

Jeune thoracic dystrophy

Pathogenic:1

Sep 28, 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 histidine, which is basic and polar, at codon 3374 of the DYNC2H1 protein (p.Arg3374His). This variant is present in population databases (rs759549373, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of Jeune syndrome (PMID: 26938784, 28832562, 29453417; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 369660). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DYNC2H1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg3374 amino acid residue in DYNC2H1. Other variant(s) that disrupt this residue have been observed in individuals with DYNC2H1-related conditions (PMID: 29068549), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

May 22, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DYNC2H1 c.10121G>A (p.Arg3374His) results in a non-conservative amino acid change located in the Dynein heavy chain, tail (IPR013594) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 6e-05 in 248894 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia (6e-05 vs 0.0025), allowing no conclusion about variant significance. c.10121G>A has been observed in individual(s) affected with Short-rib thoracic dysplasia (Stark_2016, internal_testing). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26938784, 30190612, 29453417). ClinVar contains an entry for this variant (Variation ID: 369660). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Dec 10, 2024

GeneDx

Significance:Uncertain significance

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: 34426522, 31589614, 30190612, 28832562, 29453417, 26938784) -

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Likely benign

Review Status:flagged submission

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

D;D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D;.;D

M_CAP

Benign

0.069

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Benign

-0.42

MutationAssessor

Pathogenic

3.0

M;M;.;.

PhyloP100

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.8

D;.;.;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0030

D;.;.;D

Sift4G

Uncertain

0.0090

D;.;.;D

Polyphen

1.0

D;D;D;D

Vest4

0.98

MVP

0.66

MPC

0.41

ClinPred

0.92

GERP RS

6.1

Varity_R

0.80

gMVP

0.71

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

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rs759549373

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over