rs771487311

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_001080463.2(DYNC2H1):c.10343T>C(p.Leu3448Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000852 in 1,549,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:2

Conservation

PhyloP100: 7.86

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.929

PP5

Variant 11-103255530-T-C is Pathogenic according to our data. Variant chr11-103255530-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 369661.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.10343T>C	p.Leu3448Pro	missense_variant	68/90	ENST00000650373.2
DYNC2H1	NM_001377.3 linkuse as main transcript	c.10322T>C	p.Leu3441Pro	missense_variant	67/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2 linkuse as main transcript	c.10343T>C	p.Leu3448Pro	missense_variant	68/90		NM_001080463.2	A1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.10322T>C	p.Leu3441Pro	missense_variant	67/89	1	NM_001377.3	P3	Q8NCM8-1
DYNC2H1	ENST00000334267.11 linkuse as main transcript	c.2205+121111T>C		intron_variant		1			Q8NCM8-3
	ENST00000649070.1 linkuse as main transcript	n.691-3226A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152154

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000192

AC:

AN:

156656

Hom.:

AF XY:

0.00

AC XY:

AN XY:

82320

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000481

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000881

AC:

123

AN:

1396910

Hom.:

Cov.:

AF XY:

0.0000784

AC XY:

AN XY:

689030

show subpopulations

Gnomad4 AFR exome

AF:

0.0000636

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000399

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.0000690

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000272

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 3

Pathogenic:3Uncertain: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 a leucine to a proline at amino acid position 3448, NP_001073932.1(DYNC2H1): p.Leu3448). The leucine at this position is highly conserved and is located in the ATP-binding dynein motor region D5.Grantham assessment is likely deleterious due to conservation and amino acid properties. 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 teh DYNC2H1 gene was present in trans. -
Uncertain significance, no assertion criteria provided	research	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -

Jeune thoracic dystrophy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 14, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 3448 of the DYNC2H1 protein (p.Leu3448Pro). This variant is present in population databases (rs771487311, gnomAD 0.005%). This missense change has been observed in individual(s) with DYNC2H1-related conditions (PMID: 24183451, 26938784, 29068549). 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: 369661). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -

Short-rib thoracic dysplasia 6 with or without polydactyly

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 17, 2021	PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34040173, 26938784, 28832562, 24183451, 29068549, 29453417, 27535533, 36442996, Buchh2023[Abstract]) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.33

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

4.5

H;H;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.5

D;.;.;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;.;.;D

Sift4G

Pathogenic

0.0010

D;.;.;D

Polyphen

1.0

D;D;D;D

Vest4

0.98

MVP

0.89

MPC

0.48

ClinPred

1.0

GERP RS

5.5

Varity_R

0.98

gMVP

0.94

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