rs77738279

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.2454G>A(p.Glu818Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 1,612,950 control chromosomes in the GnomAD database, including 1,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 107 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1671 hom. )

Consequence

DYNC2H1
NM_001080463.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.130

Publications

8 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=-0.75).

BP6

Variant 11-103135828-G-A is Benign according to our data. Variant chr11-103135828-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.13 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.2454G>A	p.Glu818Glu	synonymous_variant	Exon 17 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3 link	c.2454G>A	p.Glu818Glu	synonymous_variant	Exon 17 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.2454G>A	p.Glu818Glu	synonymous_variant	Exon 17 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7 link	c.2454G>A	p.Glu818Glu	synonymous_variant	Exon 17 of 89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes

AF:

0.0334

AC:

5087

AN:

152094

Hom.:

107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00775

Gnomad AMI

AF:

0.0725

Gnomad AMR

AF:

0.0286

Gnomad ASJ

AF:

0.0320

Gnomad EAS

AF:

0.0644

Gnomad SAS

AF:

0.0694

Gnomad FIN

AF:

0.0359

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0445

Gnomad OTH

AF:

0.0322

GnomAD2 exomes

AF:

0.0412

AC:

10208

AN:

247832

AF XY:

0.0442

show subpopulations

Gnomad AFR exome

AF:

0.00648

Gnomad AMR exome

AF:

0.0204

Gnomad ASJ exome

AF:

0.0336

Gnomad EAS exome

AF:

0.0614

Gnomad FIN exome

AF:

0.0367

Gnomad NFE exome

AF:

0.0430

Gnomad OTH exome

AF:

0.0419

GnomAD4 exome

AF:

0.0453

AC:

66183

AN:

1460738

Hom.:

1671

Cov.:

AF XY:

0.0465

AC XY:

33772

AN XY:

726554

show subpopulations

African (AFR)

AF:

0.00619

AC:

207

AN:

33462

American (AMR)

AF:

0.0208

AC:

925

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.0337

AC:

881

AN:

26116

East Asian (EAS)

AF:

0.0773

AC:

3063

AN:

39644

South Asian (SAS)

AF:

0.0663

AC:

5712

AN:

86110

European-Finnish (FIN)

AF:

0.0366

AC:

1951

AN:

53310

Middle Eastern (MID)

AF:

0.0342

AC:

197

AN:

5762

European-Non Finnish (NFE)

AF:

0.0456

AC:

50665

AN:

1111450

Other (OTH)

AF:

0.0428

AC:

2582

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

3244

6488

9731

12975

16219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1938

3876

5814

7752

9690

<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:

0.0334

AC:

5087

AN:

152212

Hom.:

107

Cov.:

AF XY:

0.0335

AC XY:

2494

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00773

AC:

321

AN:

41550

American (AMR)

AF:

0.0285

AC:

436

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0320

AC:

111

AN:

3472

East Asian (EAS)

AF:

0.0645

AC:

334

AN:

5176

South Asian (SAS)

AF:

0.0695

AC:

334

AN:

4808

European-Finnish (FIN)

AF:

0.0359

AC:

381

AN:

10606

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0445

AC:

3025

AN:

68016

Other (OTH)

AF:

0.0318

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

254

507

761

1014

1268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0383

Hom.:

Bravo

AF:

0.0308

Asia WGS

AF:

0.0600

AC:

208

AN:

3476

EpiCase

AF:

0.0461

EpiControl

AF:

0.0485

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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 -

May 19, 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. -

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Asphyxiating thoracic dystrophy 3

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

3.3

(source)

DANN

Benign

0.49

PhyloP100

-0.13

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