rs759549373

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_001080463.2(DYNC2H1):c.10121G>A(p.Arg3374His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,612,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3374C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:1

Conservation

PhyloP100: 9.99

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a strand (size 5) in uniprot entity DYHC2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001080463.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-103253341-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446545.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.10121G>A	p.Arg3374His	missense_variant	67/90	ENST00000650373.2
DYNC2H1	NM_001377.3 linkuse as main transcript	c.10100G>A	p.Arg3367His	missense_variant	66/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2 linkuse as main transcript	c.10121G>A	p.Arg3374His	missense_variant	67/90		NM_001080463.2	A1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.10100G>A	p.Arg3367His	missense_variant	66/89	1	NM_001377.3	P3	Q8NCM8-1
DYNC2H1	ENST00000334267.11 linkuse as main transcript	c.2205+118923G>A		intron_variant		1			Q8NCM8-3
	ENST00000649070.1 linkuse as main transcript	n.691-1038C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000603

AC:

AN:

248894

Hom.:

AF XY:

0.0000741

AC XY:

AN XY:

135024

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461024

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

726776

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74196

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000414

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Jeune thoracic dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3374 of the DYNC2H1 protein (p.Arg3374His). This variant is present in population databases (rs759549373, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of Jeune syndrome (PMID: 26938784, 28832562, 29453417; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 369660). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYNC2H1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg3374 amino acid residue in DYNC2H1. Other variant(s) that disrupt this residue have been observed in individuals with DYNC2H1-related conditions (PMID: 29068549), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Asphyxiating thoracic dystrophy 3

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 11, 2014

This substitution is predicted to create a change of an arginine to a histidine at amino acid position 3374, NP_001073932.1(DYNC2H1): p.Arg3374His). The arginine at this position is highly conserved and is located in the ATP-binding dynein motor region D5. In-silico software predicts this variant to be disease-causing. this is a novel variant not present in disease or population databases. It was identified in a patient with clinical and radiographic features of JATD, and a second novel missense variant in the DYNC2H1 gene was present in trans. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 26, 2023

Variant summary: DYNC2H1 c.10121G>A (p.Arg3374His) results in a non-conservative amino acid change located in the Dynein heavy chain, tail (IPR013594) of the encoded protein sequence. Another missense variant (p.Arg3374Cys) affecting the same residue has been classified as pathogenic/likely pathogenic by ClinVar submitters. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 248894 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia (6e-05 vs 0.0025), allowing no conclusion about variant significance. c.10121G>A has been reported in the literature in an individual affected with features of Jeune asphyxiating thoracic dystrophy (Stark_2016), and the variant was found in trans with another DYNC2H1 variant that has been classified as likely pathogenic by ClinVar submitters. These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26938784, 30190612). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Intellectual disability

Benign:1

Likely benign, flagged submission

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

D;D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D;.;D

M_CAP

Benign

0.069

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Benign

-0.42

MutationAssessor

Pathogenic

3.0

M;M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.8

D;.;.;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0030

D;.;.;D

Sift4G

Uncertain

0.0090

D;.;.;D

Polyphen

1.0

D;D;D;D

Vest4

0.98

MVP

0.66

MPC

0.41

ClinPred

0.92

GERP RS

6.1

Varity_R

0.80

gMVP

0.71

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over