rs758727391

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001080463.2(DYNC2H1):c.11291A>G(p.Gln3764Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,612,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:3

Conservation

PhyloP100: 9.18

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3100356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.11291A>G	p.Gln3764Arg	missense_variant	Exon 78 of 90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 link	c.11270A>G	p.Gln3757Arg	missense_variant	Exon 77 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.11291A>G	p.Gln3764Arg	missense_variant	Exon 78 of 90		NM_001080463.2	ENSP00000497174.1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 link	c.11270A>G	p.Gln3757Arg	missense_variant	Exon 77 of 89	1	NM_001377.3	ENSP00000364887.2	Q8NCM8-1
DYNC2H1	ENST00000334267.11 link	c.2206-131335A>G		intron_variant	Intron 15 of 19	1		ENSP00000334021.7	Q8NCM8-3
DYNC2H1	ENST00000528670.5 link	n.449A>G		non_coding_transcript_exon_variant	Exon 5 of 17	5		ENSP00000433451.1	H0YDE0

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000218

AC:

AN:

248048

AF XY:

0.000178

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00155

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1460124

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

726350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33436

American (AMR)

AF:

0.00141

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

86078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110916

Other (OTH)

AF:

0.00

AC:

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.000262

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

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:

0.0000712

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Jeune thoracic dystrophy

Pathogenic:2Uncertain:1

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Jul 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 3764 of the DYNC2H1 protein (p.Gln3764Arg). This variant is present in population databases (rs758727391, gnomAD 0.2%). This missense change has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446580). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Sep 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DYNC2H1 c.11291A>G (p.Gln3764Arg) results in a conservative amino acid change located in the Dynein heavy chain region D6 P-loop domain (IPR004273) of the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 248048 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia (0.00022 vs 0.0025), allowing no conclusion about variant significance. c.11291A>G has been reported in the literature in an individual diagnosed with asphyxiating thoracic dystrophy (ATD) (Zhang_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Short-rib thoracic dysplasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446580). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Asphyxiating thoracic dystrophy 3

Uncertain:1

Oct 11, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DYNC2H1 c.11291A>G; p.Gln3764Arg variant (rs758727391) is published in the literature in a neonate with asphyxiating thoracic dystrophy who also carried another missense DYNCH2H1 variant on the opposite chromosome (Zhang 2018). The variant is reported in the ClinVar database (Variation ID: 446580) and is found in the Latino population with an allele frequency of 0.155% (53/34,282 alleles) in the Genome Aggregation Database. The glutamine at codon 3764 is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.555) Due to limited information, the clinical significance of the p.Gln3764Arg variant is uncertain at this time. References: Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. PMID: 29068549. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

.;D;.;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.1

M;M;.;.

PhyloP100

9.2

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.9

D;.;.;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.020

D;.;.;D

Sift4G

Uncertain

0.034

D;.;.;D

Polyphen

0.98

D;D;D;D

Vest4

0.85

MutPred

0.72

Gain of MoRF binding (P = 0.1435);Gain of MoRF binding (P = 0.1435);.;.;

MVP

0.63

MPC

0.31

ClinPred

0.37

GERP RS

5.4

Varity_R

0.78

gMVP

0.61

Mutation Taster

=20/80

disease causing

(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