chr11-103166014-C-G

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.4728C>G(p.Asn1576Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0294 in 1,532,380 control chromosomes in the GnomAD database, including 804 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 (★★). Synonymous variant affecting the same amino acid position (i.e. N1576N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.023 ( 59 hom., cov: 32)

Exomes 𝑓: 0.030 ( 745 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.193

Publications

11 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=0.0019398034).

BP6

Variant 11-103166014-C-G is Benign according to our data. Variant chr11-103166014-C-G is described in ClinVar as Benign. ClinVar VariationId is 379420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0233 (3541/152226) while in subpopulation NFE AF = 0.0347 (2362/67994). AF 95% confidence interval is 0.0336. There are 59 homozygotes in GnomAd4. There are 1695 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 59 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.4728C>G	p.Asn1576Lys	missense_variant	Exon 31 of 90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 link	c.4728C>G	p.Asn1576Lys	missense_variant	Exon 31 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.4728C>G	p.Asn1576Lys	missense_variant	Exon 31 of 90		NM_001080463.2	ENSP00000497174.1		Q8NCM8-2
DYNC2H1	ENST00000375735.7 link	c.4728C>G	p.Asn1576Lys	missense_variant	Exon 31 of 89	1	NM_001377.3	ENSP00000364887.2		Q8NCM8-1

Frequencies

GnomAD3 genomes

AF:

0.0233

AC:

3542

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00546

Gnomad AMI

AF:

0.0647

Gnomad AMR

AF:

0.0303

Gnomad ASJ

AF:

0.0429

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0347

Gnomad OTH

AF:

0.0435

GnomAD2 exomes

AF:

0.0212

AC:

3057

AN:

144372

AF XY:

0.0209

show subpopulations

Gnomad AFR exome

AF:

0.00527

Gnomad AMR exome

AF:

0.0183

Gnomad ASJ exome

AF:

0.0411

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0161

Gnomad NFE exome

AF:

0.0318

Gnomad OTH exome

AF:

0.0334

GnomAD4 exome

AF:

0.0301

AC:

41525

AN:

1380154

Hom.:

745

Cov.:

AF XY:

0.0293

AC XY:

19940

AN XY:

679476

show subpopulations

African (AFR)

AF:

0.00532

AC:

165

AN:

31006

American (AMR)

AF:

0.0216

AC:

733

AN:

33890

Ashkenazi Jewish (ASJ)

AF:

0.0413

AC:

1025

AN:

24830

East Asian (EAS)

AF:

0.0000861

AC:

AN:

34828

South Asian (SAS)

AF:

0.00531

AC:

395

AN:

74398

European-Finnish (FIN)

AF:

0.0184

AC:

899

AN:

48840

Middle Eastern (MID)

AF:

0.0480

AC:

252

AN:

5254

European-Non Finnish (NFE)

AF:

0.0340

AC:

36365

AN:

1069856

Other (OTH)

AF:

0.0295

AC:

1688

AN:

57252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

1905

3809

5714

7618

9523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1406

2812

4218

5624

7030

<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:

0.0233

AC:

3541

AN:

152226

Hom.:

Cov.:

AF XY:

0.0228

AC XY:

1695

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00544

AC:

226

AN:

41532

American (AMR)

AF:

0.0302

AC:

462

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0429

AC:

149

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0150

AC:

159

AN:

10606

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0347

AC:

2362

AN:

67994

Other (OTH)

AF:

0.0435

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

182

364

545

727

909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0295

Hom.:

Bravo

AF:

0.0243

TwinsUK

AF:

0.0307

AC:

114

ALSPAC

AF:

0.0371

AC:

143

ESP6500AA

AF:

0.00779

AC:

ESP6500EA

AF:

0.0284

AC:

208

ExAC

AF:

0.00976

AC:

561

Asia WGS

AF:

0.00492

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

Sep 09, 2016

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. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, gene associated with Jeune syndrome -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Asphyxiating thoracic dystrophy 3

Benign:2

Jan 12, 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. -

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jeune thoracic dystrophy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.13

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.72

CADD

Benign

3.7

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.076

T;T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.81

.;T;.;T

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L;L;L

PhyloP100

-0.19

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.7

N;.;.;N

REVEL

Benign

0.054

Sift

Benign

0.28

T;.;.;T

Sift4G

Benign

0.12

T;.;.;T

Polyphen

0.0

B;B;B;B

Vest4

0.32

MutPred

0.37

Gain of ubiquitination at N1576 (P = 0.0114);Gain of ubiquitination at N1576 (P = 0.0114);Gain of ubiquitination at N1576 (P = 0.0114);Gain of ubiquitination at N1576 (P = 0.0114);

MPC

0.070

ClinPred

0.0032

GERP RS

-2.1

Varity_R

0.070

gMVP

0.15

Mutation Taster

=87/13

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