rs755441612

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_001080463.2(DYNC2H1):c.12460C>T(p.Arg4154Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,612,146 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. R4154H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 3.78

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_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-103436016-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2856412.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

PP5

Variant 11-103436015-C-T is Pathogenic according to our data. Variant chr11-103436015-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 387691.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.12460C>T	p.Arg4154Cys	missense_variant	Exon 86 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3 link	c.12439C>T	p.Arg4147Cys	missense_variant	Exon 85 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.12460C>T	p.Arg4154Cys	missense_variant	Exon 86 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7 link	c.12439C>T	p.Arg4147Cys	missense_variant	Exon 85 of 89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

248372

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1460144

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.0000449

AC:

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1110926

Other (OTH)

AF:

0.00

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

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:

0.0000263

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41390

American (AMR)

AF:

0.0000656

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

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:

0.0000390

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 3

Pathogenic:3

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

May 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Jeune thoracic dystrophy

Pathogenic:1

Jun 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 387691). This missense change has been observed in individual(s) with short-rib polydactyly syndrome, type III (PMID: 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs755441612, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4154 of the DYNC2H1 protein (p.Arg4154Cys). -

not specified

Uncertain:1

Oct 04, 2022

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.12460C>T (p.Arg4154Cys) results in a non-conservative amino acid change located in the C-terminal domain (IPR041228) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 248372 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.12460C>T has been reported in the literature in one individual affected with short-rib polydactyly syndrome, type 3, where it was reported as a heterozygous occurrence together with a second variant (Zhang_2018). These data do not allow any definitive conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided assessments for this variant to ClinVar after 2014. Two classified the variant as VUS and one as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Jun 01, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed with another DYNC2H1 variant, phase unknown, in an individual with short-rib polydactyly syndrome III (Zhang W et al. 2018); This variant is associated with the following publications: (PMID: 27535533, 29068549) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;.;T;.;.;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.97

.;D;D;.;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.7

M;.;M;.;.;.

PhyloP100

3.8

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.6

D;N;.;.;D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0010

D;D;.;.;D;D

Sift4G

Pathogenic

0.0010

D;D;.;.;D;D

Polyphen

1.0

D;D;D;D;D;.

Vest4

0.97

MutPred

0.85

Loss of MoRF binding (P = 0.0314);.;Loss of MoRF binding (P = 0.0314);.;.;.;

MVP

0.51

MPC

0.44

ClinPred

0.99

GERP RS

4.4

Varity_R

0.71

gMVP

0.76

Mutation Taster

=7/93

disease causing

(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