11-103117775-A-T

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.911A>T(p.Gln304Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0596 in 1,613,268 control chromosomes in the GnomAD database, including 3,207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 211 hom., cov: 32)

Exomes 𝑓: 0.061 ( 2996 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 8.88

Publications

25 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=0.002502948).

BP6

Variant 11-103117775-A-T is Benign according to our data. Variant chr11-103117775-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.911A>T	p.Gln304Leu	missense_variant	Exon 6 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3 link	c.911A>T	p.Gln304Leu	missense_variant	Exon 6 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.911A>T	p.Gln304Leu	missense_variant	Exon 6 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7 link	c.911A>T	p.Gln304Leu	missense_variant	Exon 6 of 89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes

AF:

0.0448

AC:

6815

AN:

152128

Hom.:

210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0127

Gnomad AMI

AF:

0.231

Gnomad AMR

AF:

0.0566

Gnomad ASJ

AF:

0.0649

Gnomad EAS

AF:

0.00750

Gnomad SAS

AF:

0.0532

Gnomad FIN

AF:

0.0210

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0635

Gnomad OTH

AF:

0.0641

GnomAD2 exomes

AF:

0.0493

AC:

12272

AN:

249000

AF XY:

0.0520

show subpopulations

Gnomad AFR exome

AF:

0.0104

Gnomad AMR exome

AF:

0.0440

Gnomad ASJ exome

AF:

0.0718

Gnomad EAS exome

AF:

0.00762

Gnomad FIN exome

AF:

0.0242

Gnomad NFE exome

AF:

0.0644

Gnomad OTH exome

AF:

0.0621

GnomAD4 exome

AF:

0.0611

AC:

89308

AN:

1461022

Hom.:

2996

Cov.:

AF XY:

0.0611

AC XY:

44377

AN XY:

726782

show subpopulations

African (AFR)

AF:

0.0104

AC:

349

AN:

33470

American (AMR)

AF:

0.0470

AC:

2101

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0694

AC:

1813

AN:

26112

East Asian (EAS)

AF:

0.00983

AC:

390

AN:

39672

South Asian (SAS)

AF:

0.0523

AC:

4506

AN:

86164

European-Finnish (FIN)

AF:

0.0267

AC:

1425

AN:

53364

Middle Eastern (MID)

AF:

0.0612

AC:

353

AN:

5766

European-Non Finnish (NFE)

AF:

0.0674

AC:

74940

AN:

1111440

Other (OTH)

AF:

0.0569

AC:

3431

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

4199

8398

12596

16795

20994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2808

5616

8424

11232

14040

<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:

0.0448

AC:

6817

AN:

152246

Hom.:

211

Cov.:

AF XY:

0.0443

AC XY:

3298

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0127

AC:

527

AN:

41574

American (AMR)

AF:

0.0564

AC:

863

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0649

AC:

225

AN:

3468

East Asian (EAS)

AF:

0.00752

AC:

AN:

5186

South Asian (SAS)

AF:

0.0541

AC:

261

AN:

4828

European-Finnish (FIN)

AF:

0.0210

AC:

223

AN:

10612

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0635

AC:

4319

AN:

67972

Other (OTH)

AF:

0.0644

AC:

136

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

326

653

979

1306

1632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0598

Hom.:

233

Bravo

AF:

0.0468

TwinsUK

AF:

0.0588

AC:

218

ALSPAC

AF:

0.0711

AC:

274

ESP6500AA

AF:

0.0134

AC:

ESP6500EA

AF:

0.0659

AC:

544

ExAC

AF:

0.0498

AC:

6014

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0659

EpiControl

AF:

0.0694

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Apr 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. -

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 -

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

Nov 03, 2023

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 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

0.18

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

.;T;.;T;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

D;.;D;T;.;T

MetaRNN

Benign

0.0025

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.1

.;M;M;M;M;M

PhyloP100

8.9

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.5

.;D;D;.;.;D

REVEL

Benign

0.29

Sift

Benign

0.11

.;T;T;.;.;T

Sift4G

Benign

0.33

.;T;T;.;.;T

Polyphen

0.030, 1.0, 0.087

.;B;D;B;B;B

Vest4

0.56, 0.33, 0.56

MPC

0.063

ClinPred

0.031

GERP RS

5.0

Varity_R

0.21

gMVP

0.58

Mutation Taster

=82/18

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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