rs61898615

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001080463.2(DYNC2H1):c.2860G>A(p.Glu954Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0148 in 1,565,512 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E954E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 18 hom., cov: 33)

Exomes 𝑓: 0.015 ( 208 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.92

Publications

7 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=0.0026997924).

BP6

Variant 11-103148531-G-A is Benign according to our data. Variant chr11-103148531-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 188134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0122 (1860/152220) while in subpopulation SAS AF = 0.0233 (112/4814). AF 95% confidence interval is 0.0198. There are 18 homozygotes in GnomAd4. There are 907 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.2860G>A	p.Glu954Lys	missense_variant	Exon 20 of 90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 link	c.2860G>A	p.Glu954Lys	missense_variant	Exon 20 of 89	ENST00000375735.7	NP_001368.2	Q8NCM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2 link	c.2860G>A	p.Glu954Lys	missense_variant	Exon 20 of 90		NM_001080463.2	ENSP00000497174.1		Q8NCM8-2
DYNC2H1	ENST00000375735.7 link	c.2860G>A	p.Glu954Lys	missense_variant	Exon 20 of 89	1	NM_001377.3	ENSP00000364887.2		Q8NCM8-1

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1857

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00290

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0142

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0237

Gnomad FIN

AF:

0.0176

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0169

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0163

AC:

2931

AN:

179972

AF XY:

0.0162

show subpopulations

Gnomad AFR exome

AF:

0.00298

Gnomad AMR exome

AF:

0.0306

Gnomad ASJ exome

AF:

0.00422

Gnomad EAS exome

AF:

0.000152

Gnomad FIN exome

AF:

0.0128

Gnomad NFE exome

AF:

0.0162

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.0150

AC:

21240

AN:

1413292

Hom.:

208

Cov.:

AF XY:

0.0154

AC XY:

10736

AN XY:

698332

show subpopulations

African (AFR)

AF:

0.00235

AC:

AN:

32294

American (AMR)

AF:

0.0284

AC:

1076

AN:

37844

Ashkenazi Jewish (ASJ)

AF:

0.00369

AC:

AN:

25454

East Asian (EAS)

AF:

0.0000802

AC:

AN:

37406

South Asian (SAS)

AF:

0.0238

AC:

1913

AN:

80214

European-Finnish (FIN)

AF:

0.0131

AC:

662

AN:

50424

Middle Eastern (MID)

AF:

0.0169

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0152

AC:

16526

AN:

1085380

Other (OTH)

AF:

0.0136

AC:

794

AN:

58582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

949

1897

2846

3794

4743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

590

1180

1770

2360

2950

<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:

0.0122

AC:

1860

AN:

152220

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

907

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00289

AC:

120

AN:

41558

American (AMR)

AF:

0.0145

AC:

221

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.0233

AC:

112

AN:

4814

European-Finnish (FIN)

AF:

0.0176

AC:

187

AN:

10608

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0169

AC:

1152

AN:

67998

Other (OTH)

AF:

0.0133

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

197

296

394

493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0155

Hom.:

Bravo

AF:

0.0113

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00356

AC:

ESP6500EA

AF:

0.0145

AC:

118

ExAC

AF:

0.0112

AC:

1329

Asia WGS

AF:

0.00577

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

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 24, 2017

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: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

- -

Jeune thoracic dystrophy

Benign:2

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Asphyxiating thoracic dystrophy 3

Benign:2

Nov 01, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

.;T;T;.;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.035

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.76

T;.;T;.;T

MetaRNN

Benign

0.0027

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;L;L;L;L

PhyloP100

3.9

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.8

.;D;.;.;D

REVEL

Benign

0.080

Sift

Benign

0.088

.;T;.;.;T

Sift4G

Benign

0.16

.;T;.;.;T

Polyphen

0.0, 0.0010

.;B;B;B;B

Vest4

0.086, 0.074

MPC

0.069

ClinPred

0.024

GERP RS

4.7

Varity_R

0.099

gMVP

0.27

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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