rs10129889

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001376.5(DYNC1H1):c.12087C>A(p.His4029Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0728 in 1,614,016 control chromosomes in the GnomAD database, including 6,314 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1814 hom., cov: 32)

Exomes 𝑓: 0.068 ( 4500 hom. )

Consequence

DYNC1H1
NM_001376.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.457

Publications

22 publications found

Variant links:

Genes affected

DYNC1H1 (HGNC:2961): (dynein cytoplasmic 1 heavy chain 1) Dyneins are a group of microtubule-activated ATPases that function as molecular motors. They are divided into two subgroups of axonemal and cytoplasmic dyneins. The cytoplasmic dyneins function in intracellular motility, including retrograde axonal transport, protein sorting, organelle movement, and spindle dynamics. Molecules of conventional cytoplasmic dynein are comprised of 2 heavy chain polypeptides and a number of intermediate and light chains.This gene encodes a member of the cytoplasmic dynein heavy chain family. [provided by RefSeq, Oct 2008]

DYNC1H1 Gene-Disease associations (from GenCC):

autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
intellectual disability, autosomal dominant 13
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
neuronopathy, distal hereditary motor
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease axonal type 2O
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DYNC1H1 links:

ENSG00000293472 (HGNC:):

ENSG00000293472 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=0.0016406178).

BP6

Variant 14-102041719-C-A is Benign according to our data. Variant chr14-102041719-C-A is described in ClinVar as Benign. ClinVar VariationId is 128928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1H1	NM_001376.5 link	c.12087C>A	p.His4029Gln	missense_variant	Exon 65 of 78	ENST00000360184.10	NP_001367.2	Q14204

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10 link	c.12087C>A	p.His4029Gln	missense_variant	Exon 65 of 78	1	NM_001376.5	ENSP00000348965.4		Q14204

Frequencies

GnomAD3 genomes

AF:

0.121

AC:

18430

AN:

152120

Hom.:

1815

Cov.:

show subpopulations

Gnomad AFR

AF:

0.270

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.0649

Gnomad ASJ

AF:

0.0527

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0230

Gnomad FIN

AF:

0.104

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0667

Gnomad OTH

AF:

0.113

GnomAD2 exomes

AF:

0.0693

AC:

17413

AN:

251132

AF XY:

0.0640

show subpopulations

Gnomad AFR exome

AF:

0.277

Gnomad AMR exome

AF:

0.0425

Gnomad ASJ exome

AF:

0.0429

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.0917

Gnomad NFE exome

AF:

0.0688

Gnomad OTH exome

AF:

0.0662

GnomAD4 exome

AF:

0.0678

AC:

99066

AN:

1461778

Hom.:

4500

Cov.:

AF XY:

0.0658

AC XY:

47814

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.281

AC:

9406

AN:

33480

American (AMR)

AF:

0.0455

AC:

2034

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0434

AC:

1133

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0278

AC:

2401

AN:

86258

European-Finnish (FIN)

AF:

0.0932

AC:

4969

AN:

53310

Middle Eastern (MID)

AF:

0.0565

AC:

326

AN:

5768

European-Non Finnish (NFE)

AF:

0.0669

AC:

74378

AN:

1112008

Other (OTH)

AF:

0.0731

AC:

4413

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

6332

12664

18995

25327

31659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2822

5644

8466

11288

14110

<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:

0.121

AC:

18455

AN:

152238

Hom.:

1814

Cov.:

AF XY:

0.118

AC XY:

8790

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.270

AC:

11227

AN:

41512

American (AMR)

AF:

0.0647

AC:

990

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0527

AC:

183

AN:

3470

East Asian (EAS)

AF:

0.000580

AC:

AN:

5176

South Asian (SAS)

AF:

0.0224

AC:

108

AN:

4832

European-Finnish (FIN)

AF:

0.104

AC:

1099

AN:

10610

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0667

AC:

4538

AN:

68020

Other (OTH)

AF:

0.112

AC:

236

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

745

1491

2236

2982

3727

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<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:

0.0830

Hom.:

2046

Bravo

AF:

0.126

TwinsUK

AF:

0.0585

AC:

217

ALSPAC

AF:

0.0675

AC:

260

ESP6500AA

AF:

0.272

AC:

1199

ESP6500EA

AF:

0.0621

AC:

534

ExAC

AF:

0.0740

AC:

8982

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0620

EpiControl

AF:

0.0672

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Dec 30, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Charcot-Marie-Tooth disease axonal type 2O

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 16, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 22, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal dominant cerebellar ataxia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.084

T;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.55

N;.

PhyloP100

0.46

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.2

N;.

REVEL

Benign

0.12

Sift

Benign

0.66

T;.

Polyphen

0.0010

B;.

Vest4

0.17

MutPred

0.26

Gain of helix (P = 0.132);.;

MPC

0.94

ClinPred

0.010

GERP RS

4.6

Varity_R

0.18

gMVP

0.64

Mutation Taster

=89/11

polymorphism (auto)

(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