11-103253406-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001080463.2(DYNC2H1):c.10185T>G(p.Thr3395Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,612,672 control chromosomes in the GnomAD database, including 15,438 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. T3395T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.18 ( 3005 hom., cov: 32)

Exomes 𝑓: 0.12 ( 12433 hom. )

Consequence

DYNC2H1
NM_001080463.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0130

Publications

18 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:

ENSG00000285878 (HGNC:):

ENSG00000285878 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 11-103253406-T-G is Benign according to our data. Variant chr11-103253406-T-G is described in ClinVar as [Benign]. Clinvar id is 302088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.013 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.10185T>G	p.Thr3395Thr	synonymous_variant	Exon 67 of 90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 link	c.10164T>G	p.Thr3388Thr	synonymous_variant	Exon 66 of 89	ENST00000375735.7	NP_001368.2	Q8NCM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DYNC2H1	ENST00000650373.2 link	c.10185T>G	p.Thr3395Thr	synonymous_variant	Exon 67 of 90		NM_001080463.2	ENSP00000497174.1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 link	c.10164T>G	p.Thr3388Thr	synonymous_variant	Exon 66 of 89	1	NM_001377.3	ENSP00000364887.2	Q8NCM8-1
DYNC2H1	ENST00000334267.11 link	c.2205+118987T>G		intron_variant	Intron 15 of 19	1		ENSP00000334021.7	Q8NCM8-3
ENSG00000285878	ENST00000649070.1 link	n.691-1102A>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.176

AC:

26741

AN:

151912

Hom.:

2998

Cov.:

show subpopulations

Gnomad AFR

AF:

0.321

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.0638

Gnomad EAS

AF:

0.0971

Gnomad SAS

AF:

0.109

Gnomad FIN

AF:

0.187

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.149

GnomAD2 exomes

AF:

0.128

AC:

31805

AN:

248772

AF XY:

0.123

show subpopulations

Gnomad AFR exome

AF:

0.328

Gnomad AMR exome

AF:

0.100

Gnomad ASJ exome

AF:

0.0656

Gnomad EAS exome

AF:

0.0985

Gnomad FIN exome

AF:

0.173

Gnomad NFE exome

AF:

0.116

Gnomad OTH exome

AF:

0.111

GnomAD4 exome

AF:

0.125

AC:

182198

AN:

1460640

Hom.:

12433

Cov.:

AF XY:

0.123

AC XY:

89639

AN XY:

726628

show subpopulations

African (AFR)

AF:

0.328

AC:

10973

AN:

33442

American (AMR)

AF:

0.103

AC:

4581

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.0622

AC:

1624

AN:

26110

East Asian (EAS)

AF:

0.122

AC:

4838

AN:

39626

South Asian (SAS)

AF:

0.111

AC:

9524

AN:

86174

European-Finnish (FIN)

AF:

0.167

AC:

8911

AN:

53374

Middle Eastern (MID)

AF:

0.0826

AC:

476

AN:

5762

European-Non Finnish (NFE)

AF:

0.120

AC:

133363

AN:

1111146

Other (OTH)

AF:

0.131

AC:

7908

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

7693

15386

23079

30772

38465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.176

AC:

26776

AN:

152032

Hom.:

3005

Cov.:

AF XY:

0.175

AC XY:

13037

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.321

AC:

13318

AN:

41434

American (AMR)

AF:

0.103

AC:

1581

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0638

AC:

221

AN:

3462

East Asian (EAS)

AF:

0.0971

AC:

502

AN:

5172

South Asian (SAS)

AF:

0.107

AC:

519

AN:

4830

European-Finnish (FIN)

AF:

0.187

AC:

1976

AN:

10574

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.121

AC:

8256

AN:

67960

Other (OTH)

AF:

0.149

AC:

315

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1063

2126

3189

4252

5315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.126

Hom.:

2552

Bravo

AF:

0.176

Asia WGS

AF:

0.115

AC:

398

AN:

3474

EpiCase

AF:

0.110

EpiControl

AF:

0.102

ClinVar

Significance: Benign

Submissions summary: Benign:8

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

- -

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

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

- -

Mar 29, 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: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

- -

Asphyxiating thoracic dystrophy 3

Benign:1

Jan 13, 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. -

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

-0.45

CADD

Benign

6.6

(source)

DANN

Benign

0.66

PhyloP100

0.013

Mutation Taster

=94/6

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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11-103253406-T-G

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