rs78309870

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.9353+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,593,974 control chromosomes in the GnomAD database, including 332 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 180 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 152 hom. )

Consequence

DYNC2H1
NM_001080463.2 splice_region, intron

Scores

Splicing: ADA: 0.00007715

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.362

Publications

3 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 (BayesDel_noAF=-0.8).

BP6

Variant 11-103223093-G-A is Benign according to our data. Variant chr11-103223093-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.9353+7G>A		splice_region_variant, intron_variant	Intron 59 of 89	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 link	c.9353+7G>A		splice_region_variant, intron_variant	Intron 59 of 88	ENST00000375735.7	NP_001368.2	Q8NCM8-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DYNC2H1	ENST00000650373.2 link	c.9353+7G>A	splice_region_variant, intron_variant	Intron 59 of 89		NM_001080463.2	ENSP00000497174.1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 link	c.9353+7G>A	splice_region_variant, intron_variant	Intron 59 of 88	1	NM_001377.3	ENSP00000364887.2	Q8NCM8-1
DYNC2H1	ENST00000334267.11 link	c.2205+88674G>A	intron_variant	Intron 15 of 19	1		ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes

AF:

0.0264

AC:

4010

AN:

152056

Hom.:

180

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0897

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.00748

AC:

1628

AN:

217636

AF XY:

0.00571

show subpopulations

Gnomad AFR exome

AF:

0.0932

Gnomad AMR exome

AF:

0.00632

Gnomad ASJ exome

AF:

0.00585

Gnomad EAS exome

AF:

0.00228

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000799

Gnomad OTH exome

AF:

0.00551

GnomAD4 exome

AF:

0.00316

AC:

4553

AN:

1441800

Hom.:

152

Cov.:

AF XY:

0.00285

AC XY:

2040

AN XY:

715814

show subpopulations

African (AFR)

AF:

0.0920

AC:

3024

AN:

32860

American (AMR)

AF:

0.00684

AC:

287

AN:

41948

Ashkenazi Jewish (ASJ)

AF:

0.00533

AC:

137

AN:

25690

East Asian (EAS)

AF:

0.00174

AC:

AN:

38562

South Asian (SAS)

AF:

0.000263

AC:

AN:

83646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52362

Middle Eastern (MID)

AF:

0.00771

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.000468

AC:

516

AN:

1101446

Other (OTH)

AF:

0.00765

AC:

456

AN:

59578

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

187

373

560

746

933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.0264

AC:

4019

AN:

152174

Hom.:

180

Cov.:

AF XY:

0.0249

AC XY:

1856

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0897

AC:

3722

AN:

41516

American (AMR)

AF:

0.0107

AC:

164

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3466

East Asian (EAS)

AF:

0.00270

AC:

AN:

5176

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000853

AC:

AN:

68010

Other (OTH)

AF:

0.0199

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

192

383

575

766

958

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.00973

Hom.:

Bravo

AF:

0.0303

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Aug 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

- -

not provided

Benign:2

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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. -

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:Likely 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

-0.80

CADD

Benign

6.1

(source)

DANN

Benign

0.52

PhyloP100

0.36

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000077

dbscSNV1_RF

Benign

0.0

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