rs189806840

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001080463.2(DYNC2H1):c.3682C>A(p.Leu1228Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,612,340 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1228L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 6 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:12B:3

Conservation

PhyloP100: 1.09

Publications

10 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008179843).

BP6

Variant 11-103155439-C-A is Benign according to our data. Variant chr11-103155439-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238270.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0018 (274/151988) while in subpopulation AMR AF = 0.00505 (77/15258). AF 95% confidence interval is 0.00414. There are 0 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.3682C>A	p.Leu1228Ile	missense_variant	Exon 25 of 90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 link	c.3682C>A	p.Leu1228Ile	missense_variant	Exon 25 of 89	ENST00000375735.7	NP_001368.2	Q8NCM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2 link	c.3682C>A	p.Leu1228Ile	missense_variant	Exon 25 of 90		NM_001080463.2	ENSP00000497174.1		Q8NCM8-2
DYNC2H1	ENST00000375735.7 link	c.3682C>A	p.Leu1228Ile	missense_variant	Exon 25 of 89	1	NM_001377.3	ENSP00000364887.2		Q8NCM8-1

Frequencies

GnomAD3 genomes

AF:

0.00180

AC:

274

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000581

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00505

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000949

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00162

AC:

402

AN:

247758

AF XY:

0.00169

show subpopulations

Gnomad AFR exome

AF:

0.000909

Gnomad AMR exome

AF:

0.00283

Gnomad ASJ exome

AF:

0.0000997

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00238

Gnomad OTH exome

AF:

0.00317

GnomAD4 exome

AF:

0.00233

AC:

3398

AN:

1460352

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

1678

AN XY:

726444

show subpopulations

African (AFR)

AF:

0.000628

AC:

AN:

33416

American (AMR)

AF:

0.00343

AC:

153

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26096

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39604

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86022

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00273

AC:

3037

AN:

1111156

Other (OTH)

AF:

0.00280

AC:

169

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

183

366

549

732

915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<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:

0.00180

AC:

274

AN:

151988

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

118

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.000579

AC:

AN:

41464

American (AMR)

AF:

0.00505

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000949

AC:

AN:

10534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00240

AC:

163

AN:

67960

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.00215

Hom.:

Bravo

AF:

0.00229

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000545

AC:

ESP6500EA

AF:

0.00171

AC:

ExAC

AF:

0.00136

AC:

164

EpiCase

AF:

0.00284

EpiControl

AF:

0.00256

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:12Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6Benign:1

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 20, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DYNC2H1 p.Leu1228Ile variant was identified in 4 of 446 proband chromosomes (frequency: 0.00897) from individuals or families with short-rib polydactyly syndromes (SRPS), asphyxiating thoracic dystrophy (ATD) or Ellis van Creveld (EVC) syndrome (Schmidts_2013_PMID:23456818; Zhang_2018_PMID:29068549). The variant was also identified in dbSNP (ID: rs189806840), ClinVar (classified as likely benign by Invitae and GeneDx, a VUS by 4 labs and pathogenic by Dan Cohn Lab,University Of California Los Angeles) and LOVD 3.0. The variant was not identified in Cosmic. The variant was identified in control databases in 442 of 279018 chromosomes at a frequency of 0.001584 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 21 of 7080 chromosomes (freq: 0.002966), Latino in 104 of 35140 chromosomes (freq: 0.00296), European (non-Finnish) in 290 of 127576 chromosomes (freq: 0.002273), African in 22 of 24080 chromosomes (freq: 0.000914), European (Finnish) in 4 of 24956 chromosomes (freq: 0.00016) and Ashkenazi Jewish in 1 of 10318 chromosomes (freq: 0.000097), while the variant was not observed in the East Asian and South Asian populations. The p.Leu1228 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Jul 23, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29068549, 2687404, 23456818, 26874042, 30755392) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jeune thoracic dystrophy

Pathogenic:2Benign:1

Jan 21, 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

- -

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Asphyxiating thoracic dystrophy 3

Uncertain:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Dec 07, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DYNC2H1 c.3682C>A; p.Leu1228Ile variant (rs189806840) is reported in the literature in individuals affected with asphyxiating thoracic dysplasia, several of whom carried additional variants in the DYNC2H1 gene (Cossu 2016, Schmidts 2013, Zhang 2018). The p.Leu1228Ile variant is found in the Latino population with an overall allele frequency of 0.30% (104/35140 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 238270). The leucine at codon 1228 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Leu1228Ile variant is uncertain at this time. References: Cossu C et al. New mutations in DYNC2H1 and WDR60 genes revealed by whole-exome sequencing in two unrelated Sardinian families with Jeune asphyxiating thoracic dystrophy. Clin Chim Acta. 2016 Apr 1;455:172-80. Schmidts M et al. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. J Med Genet. 2013 May;50(5):309-23. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. -

Aug 23, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Uncertain:1Benign:1

Oct 20, 2020

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 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.3682C>A (p.Leu1228Ile) results in a conservative amino acid change located in the Dynein heavy chain, linker region (IPR013602) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 247758 control chromosomes, predominantly at a frequency of 0.0028 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia phenotype (0.0025). c.3682C>A has been reported in the literature in individuals affected with features of Short-rib thoracic dysplasia/Asphyxiating thoracic dystrophy (Zhang_2018, Schmitds_2013, Cossu_2016, Cloney_2022), and some of these individuals had a (likely) pathogenic variants in trans, although in another case additional variants in the DYNC2H1 gene were also noted. 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: 29068549, 34740920, 26874042, 23456818). ClinVar contains an entry for this variant (Variation ID: 238270). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Optic atrophy

Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

.;T;T;.;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.88

D;.;D;.;D

M_CAP

Benign

0.071

MetaRNN

Benign

0.0082

T;T;T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.2

.;M;M;M;M

PhyloP100

1.1

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.6

.;N;.;.;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.012

.;D;.;.;D

Sift4G

Uncertain

0.018

.;D;.;.;D

Polyphen

0.99, 1.0

.;D;D;D;D

Vest4

0.53, 0.52

MVP

0.62

MPC

0.36

ClinPred

0.023

GERP RS

-1.0

Varity_R

0.35

gMVP

0.38

Mutation Taster

=72/28

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