rs775615484

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001080463.2(DYNC2H1):c.10220G>A(p.Arg3407Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000158 in 1,612,074 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 4.17

Publications

0 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.073687166).

BP6

Variant 11-103253441-G-A is Benign according to our data. Variant chr11-103253441-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290764.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.10220G>A	p.Arg3407Gln	missense_variant	Exon 67 of 90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3 link	c.10199G>A	p.Arg3400Gln	missense_variant	Exon 66 of 89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DYNC2H1	ENST00000650373.2 link	c.10220G>A	p.Arg3407Gln	missense_variant	Exon 67 of 90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7 link	c.10199G>A	p.Arg3400Gln	missense_variant	Exon 66 of 89	1	NM_001377.3	ENSP00000364887.2
DYNC2H1	ENST00000334267.11 link	c.2205+119022G>A		intron_variant	Intron 15 of 19	1		ENSP00000334021.7
ENSG00000285878	ENST00000649070.1 link	n.691-1137C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000125

AC:

AN:

248526

AF XY:

0.000126

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000222

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000152

AC:

222

AN:

1460010

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

123

AN XY:

726288

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33438

American (AMR)

AF:

0.0000224

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86028

European-Finnish (FIN)

AF:

0.000375

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000168

AC:

187

AN:

1110768

Other (OTH)

AF:

0.0000829

AC:

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000217

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000215

Hom.:

Bravo

AF:

0.000166

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.10220G>A (p.R3407Q) alteration is located in exon 67 (coding exon 67) of the DYNC2H1 gene. This alteration results from a G to A substitution at nucleotide position 10220, causing the arginine (R) at amino acid position 3407 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Sep 01, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Asphyxiating thoracic dystrophy 3

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jeune thoracic dystrophy

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.038

T;T;.;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

.;D;.;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.074

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.63

N;N;.;.

PhyloP100

4.2

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.32

N;.;.;N

REVEL

Benign

0.051

Sift

Benign

0.29

T;.;.;T

Sift4G

Benign

0.48

T;.;.;T

Polyphen

0.0

B;B;B;B

Vest4

0.34

MVP

0.28

MPC

0.070

ClinPred

0.049

GERP RS

4.8

Varity_R

0.13

gMVP

0.48

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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