11-103186319-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001080463.2(DYNC2H1):c.6711A>G(p.Arg2237Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,612,044 control chromosomes in the GnomAD database, including 302,784 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R2237R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.60 ( 27305 hom., cov: 30)

Exomes 𝑓: 0.61 ( 275479 hom. )

Consequence

DYNC2H1
NM_001080463.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.276

Publications

21 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 11-103186319-A-G is Benign according to our data. Variant chr11-103186319-A-G is described in ClinVar as Benign. ClinVar VariationId is 302056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.276 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.6711A>G	p.Arg2237Arg	synonymous_variant	Exon 42 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3 link	c.6711A>G	p.Arg2237Arg	synonymous_variant	Exon 42 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.6711A>G	p.Arg2237Arg	synonymous_variant	Exon 42 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7 link	c.6711A>G	p.Arg2237Arg	synonymous_variant	Exon 42 of 89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes

AF:

0.597

AC:

90442

AN:

151500

Hom.:

27276

Cov.:

show subpopulations

Gnomad AFR

AF:

0.528

Gnomad AMI

AF:

0.458

Gnomad AMR

AF:

0.693

Gnomad ASJ

AF:

0.675

Gnomad EAS

AF:

0.551

Gnomad SAS

AF:

0.546

Gnomad FIN

AF:

0.622

Gnomad MID

AF:

0.659

Gnomad NFE

AF:

0.618

Gnomad OTH

AF:

0.597

GnomAD2 exomes

AF:

0.627

AC:

155479

AN:

248044

AF XY:

0.622

show subpopulations

Gnomad AFR exome

AF:

0.522

Gnomad AMR exome

AF:

0.761

Gnomad ASJ exome

AF:

0.665

Gnomad EAS exome

AF:

0.542

Gnomad FIN exome

AF:

0.631

Gnomad NFE exome

AF:

0.628

Gnomad OTH exome

AF:

0.631

GnomAD4 exome

AF:

0.612

AC:

894337

AN:

1460426

Hom.:

275479

Cov.:

AF XY:

0.611

AC XY:

443527

AN XY:

726482

show subpopulations

African (AFR)

AF:

0.525

AC:

17555

AN:

33438

American (AMR)

AF:

0.750

AC:

33462

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.672

AC:

17518

AN:

26080

East Asian (EAS)

AF:

0.504

AC:

19954

AN:

39618

South Asian (SAS)

AF:

0.557

AC:

48017

AN:

86226

European-Finnish (FIN)

AF:

0.628

AC:

33487

AN:

53310

Middle Eastern (MID)

AF:

0.640

AC:

3687

AN:

5764

European-Non Finnish (NFE)

AF:

0.615

AC:

683849

AN:

1111076

Other (OTH)

AF:

0.610

AC:

36808

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

20159

40318

60476

80635

100794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18332

36664

54996

73328

91660

<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:

0.597

AC:

90515

AN:

151618

Hom.:

27305

Cov.:

AF XY:

0.597

AC XY:

44218

AN XY:

74052

show subpopulations

African (AFR)

AF:

0.528

AC:

21824

AN:

41352

American (AMR)

AF:

0.694

AC:

10538

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

0.675

AC:

2338

AN:

3462

East Asian (EAS)

AF:

0.552

AC:

2835

AN:

5134

South Asian (SAS)

AF:

0.547

AC:

2629

AN:

4804

European-Finnish (FIN)

AF:

0.622

AC:

6559

AN:

10542

Middle Eastern (MID)

AF:

0.661

AC:

193

AN:

292

European-Non Finnish (NFE)

AF:

0.618

AC:

41918

AN:

67826

Other (OTH)

AF:

0.600

AC:

1264

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1834

3667

5501

7334

9168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

756

1512

2268

3024

3780

<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:

0.612

Hom.:

17622

Bravo

AF:

0.601

EpiCase

AF:

0.631

EpiControl

AF:

0.635

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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. -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Short rib-polydactyly syndrome

Benign:1

Jun 14, 2016

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

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.68

(source)

DANN

Benign

0.35

PhyloP100

-0.28

Mutation Taster

=100/0

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