rs368058473

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001080463.2(DYNC2H1):c.5821G>C(p.Ala1941Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000396 in 1,592,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: -0.112

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06887221).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.5821G>C	p.Ala1941Pro	missense_variant	Exon 37 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3 link	c.5821G>C	p.Ala1941Pro	missense_variant	Exon 37 of 89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2 link	c.5821G>C	p.Ala1941Pro	missense_variant	Exon 37 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7 link	c.5821G>C	p.Ala1941Pro	missense_variant	Exon 37 of 89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000590

AC:

AN:

220478

AF XY:

0.0000421

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000167

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000696

Gnomad OTH exome

AF:

0.000186

GnomAD4 exome

AF:

0.0000382

AC:

AN:

1440392

Hom.:

Cov.:

AF XY:

0.0000308

AC XY:

AN XY:

714490

show subpopulations

African (AFR)

AF:

0.0000307

AC:

AN:

32594

American (AMR)

AF:

0.000240

AC:

AN:

41750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25716

East Asian (EAS)

AF:

0.00

AC:

AN:

38760

South Asian (SAS)

AF:

0.00

AC:

AN:

81010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.0000299

AC:

AN:

1102578

Other (OTH)

AF:

0.000184

AC:

AN:

59648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000526

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.000131

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000141

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000245

AC:

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Dec 22, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Observed with a likely pathogenic variant on the opposite allele (in trans) in a patient referred for genetic testing at GeneDx with clinical features suggestive of a skeletal dysplasia

Apr 27, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

Sep 12, 2019

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DYNC2H1-related disorder

Uncertain:1

Dec 21, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DYNC2H1 c.5821G>C variant is predicted to result in the amino acid substitution p.Ala1941Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-103047110-G-C). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Inborn genetic diseases

Uncertain:1

Sep 09, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5821G>C (p.A1941P) alteration is located in exon 37 (coding exon 37) of the DYNC2H1 gene. This alteration results from a G to C substitution at nucleotide position 5821, causing the alanine (A) at amino acid position 1941 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Jeune thoracic dystrophy

Uncertain:1

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1941 of the DYNC2H1 protein (p.Ala1941Pro). This variant is present in population databases (rs368058473, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DYNC2H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 167012). 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 not expected to disrupt DYNC2H1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.083

T;T;.;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.0

.;T;.;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.069

T;T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.9

L;L;L;L

PhyloP100

-0.11

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.6

N;.;.;N

REVEL

Uncertain

0.39

Sift

Benign

0.25

T;.;.;T

Sift4G

Benign

0.21

T;.;.;T

Vest4

0.42

ClinPred

0.025

GERP RS

-3.2

Varity_R

0.24

gMVP

0.48

Mutation Taster

=60/40

polymorphism

(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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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