rs146569005

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001080463.2(DYNC2H1):c.7319C>T(p.Thr2440Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000732 in 1,612,696 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2440T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0040 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 7 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.99

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

DYNC2H1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010034293).

BP6

Variant 11-103189698-C-T is Benign according to our data. Variant chr11-103189698-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00397 (604/152118) while in subpopulation AFR AF = 0.0139 (577/41504). AF 95% confidence interval is 0.013. There are 2 homozygotes in GnomAd4. There are 287 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.7319C>T	p.Thr2440Met	missense_variant	Exon 45 of 90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 link	c.7319C>T	p.Thr2440Met	missense_variant	Exon 45 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.7319C>T	p.Thr2440Met	missense_variant	Exon 45 of 90		NM_001080463.2	ENSP00000497174.1		Q8NCM8-2
DYNC2H1	ENST00000375735.7 link	c.7319C>T	p.Thr2440Met	missense_variant	Exon 45 of 89	1	NM_001377.3	ENSP00000364887.2		Q8NCM8-1

Frequencies

GnomAD3 genomes

AF:

0.00396

AC:

602

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0139

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00125

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:

0.0000294

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00103

AC:

255

AN:

248040

AF XY:

0.000780

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.000465

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000801

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000394

AC:

576

AN:

1460578

Hom.:

Cov.:

AF XY:

0.000361

AC XY:

262

AN XY:

726562

show subpopulations

African (AFR)

AF:

0.0141

AC:

471

AN:

33424

American (AMR)

AF:

0.000537

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39600

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.0000940

AC:

AN:

53184

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1111334

Other (OTH)

AF:

0.000696

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00397

AC:

604

AN:

152118

Hom.:

Cov.:

AF XY:

0.00386

AC XY:

287

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0139

AC:

577

AN:

41504

American (AMR)

AF:

0.00124

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67980

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

122

152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00129

Hom.:

Bravo

AF:

0.00459

ESP6500AA

AF:

0.0145

AC:

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.00145

AC:

175

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000238

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 10, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jeune thoracic dystrophy

Benign:1

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Asphyxiating thoracic dystrophy 3

Benign:1

Apr 08, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

.;D;.;D

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.2

L;L;L;L

PhyloP100

3.0

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.9

N;.;.;N

REVEL

Benign

0.12

Sift

Benign

0.033

D;.;.;D

Sift4G

Benign

0.091

T;.;.;T

Polyphen

0.99

D;D;D;D

Vest4

0.52

MVP

0.55

MPC

0.21

ClinPred

0.017

GERP RS

5.5

Varity_R

0.16

gMVP

0.48

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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