chr11-103121378-G-A

Variant names:

Variant summary

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

The NM_001080463.2(DYNC2H1):c.1367G>A(p.Arg456Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,598,844 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 149 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 138 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.76

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001755178).

BP6

Variant 11-103121378-G-A is Benign according to our data. Variant chr11-103121378-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.1367G>A	p.Arg456Gln	missense_variant	Exon 10 of 90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 link	c.1367G>A	p.Arg456Gln	missense_variant	Exon 10 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.1367G>A	p.Arg456Gln	missense_variant	Exon 10 of 90		NM_001080463.2	ENSP00000497174.1		Q8NCM8-2
DYNC2H1	ENST00000375735.7 link	c.1367G>A	p.Arg456Gln	missense_variant	Exon 10 of 89	1	NM_001377.3	ENSP00000364887.2		Q8NCM8-1

Frequencies

GnomAD3 genomes

AF:

0.0228

AC:

3468

AN:

152026

Hom.:

149

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0790

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00858

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.0211

GnomAD2 exomes

AF:

0.00562

AC:

1297

AN:

230702

AF XY:

0.00429

show subpopulations

Gnomad AFR exome

AF:

0.0779

Gnomad AMR exome

AF:

0.00372

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000474

Gnomad NFE exome

AF:

0.000104

Gnomad OTH exome

AF:

0.00249

GnomAD4 exome

AF:

0.00236

AC:

3408

AN:

1446700

Hom.:

138

Cov.:

AF XY:

0.00203

AC XY:

1458

AN XY:

718950

show subpopulations

African (AFR)

AF:

0.0859

AC:

2803

AN:

32644

American (AMR)

AF:

0.00389

AC:

161

AN:

41440

Ashkenazi Jewish (ASJ)

AF:

0.0000782

AC:

AN:

25590

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39496

South Asian (SAS)

AF:

0.0000970

AC:

AN:

82438

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

53032

Middle Eastern (MID)

AF:

0.00334

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000795

AC:

AN:

1106638

Other (OTH)

AF:

0.00542

AC:

324

AN:

59730

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

137

275

412

550

687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.0228

AC:

3471

AN:

152144

Hom.:

149

Cov.:

AF XY:

0.0217

AC XY:

1617

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0788

AC:

3269

AN:

41486

American (AMR)

AF:

0.00857

AC:

131

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0000946

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68026

Other (OTH)

AF:

0.0208

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

160

320

480

640

800

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.00789

Hom.:

105

Bravo

AF:

0.0262

ESP6500AA

AF:

0.0760

AC:

274

ESP6500EA

AF:

0.000491

AC:

ExAC

AF:

0.00627

AC:

757

Asia WGS

AF:

0.00347

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Jeune thoracic dystrophy

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Asphyxiating thoracic dystrophy 3

Benign:2

Oct 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not specified

Benign:1

Sep 14, 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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.057

.;T;.;T;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

0.063

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.75

T;.;T;T;.;T

MetaRNN

Benign

0.0018

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.60

.;N;N;N;N;N

PhyloP100

1.8

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.47

.;N;N;.;.;N

REVEL

Benign

0.062

Sift

Benign

0.91

.;T;T;.;.;T

Sift4G

Benign

0.85

.;T;T;.;.;T

Polyphen

0.0010, 0.20, 0.0

.;B;B;B;B;B

Vest4

0.13, 0.14, 0.12

MVP

0.58

MPC

0.070

ClinPred

0.0076

GERP RS

5.4

Varity_R

0.033

gMVP

0.20

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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