rs562139820

Positions:

chr11-103257731-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001377.3(DYNC2H1):c.10585C>T(p.Arg3529*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,598,978 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

DYNC2H1
NM_001377.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 0.648

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:

ENSG00000285878 (HGNC:):

ENSG00000285878 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-103257731-C-T is Pathogenic according to our data. Variant chr11-103257731-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 407155.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-103257731-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.10606C>T	p.Arg3536*	stop_gained	70/90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 linkuse as main transcript	c.10585C>T	p.Arg3529*	stop_gained	69/89	ENST00000375735.7	NP_001368.2	Q8NCM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DYNC2H1	ENST00000650373.2 linkuse as main transcript	c.10606C>T	p.Arg3536*	stop_gained	70/90		NM_001080463.2	ENSP00000497174.1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.10585C>T	p.Arg3529*	stop_gained	69/89	1	NM_001377.3	ENSP00000364887.2	Q8NCM8-1
DYNC2H1	ENST00000334267.11 linkuse as main transcript	c.2205+123312C>T		intron_variant		1		ENSP00000334021.7	Q8NCM8-3
ENSG00000285878	ENST00000649070.1 linkuse as main transcript	n.691-5427G>A		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000553

AC:

AN:

1446738

Hom.:

Cov.:

AF XY:

0.00000696

AC XY:

AN XY:

718480

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000634

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 3

Pathogenic:2

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

Jeune thoracic dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2023

This sequence change creates a premature translational stop signal (p.Arg3536*) in the DYNC2H1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYNC2H1 are known to be pathogenic (PMID: 23339108, 32753734, 33755199). This variant is present in population databases (rs562139820, gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 23339108). ClinVar contains an entry for this variant (Variation ID: 407155). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.81

Vest4

0.95

GERP RS

0.28

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