rs181011657

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001080463.2(DYNC2H1):c.10594C>T(p.Arg3532Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000399 in 1,604,004 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 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.98

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 Pathogenic. Variant got 18 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 11-103257719-C-T is Pathogenic according to our data. Variant chr11-103257719-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 446570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103257719-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.10594C>T	p.Arg3532Ter	stop_gained	70/90	ENST00000650373.2
DYNC2H1	NM_001377.3 linkuse as main transcript	c.10573C>T	p.Arg3525Ter	stop_gained	69/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2 linkuse as main transcript	c.10594C>T	p.Arg3532Ter	stop_gained	70/90		NM_001080463.2	A1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.10573C>T	p.Arg3525Ter	stop_gained	69/89	1	NM_001377.3	P3	Q8NCM8-1
DYNC2H1	ENST00000334267.11 linkuse as main transcript	c.2205+123300C>T		intron_variant		1			Q8NCM8-3
	ENST00000649070.1 linkuse as main transcript	n.691-5415G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

236494

Hom.:

AF XY:

0.0000469

AC XY:

AN XY:

128032

show subpopulations

Gnomad AFR exome

AF:

0.000692

Gnomad AMR exome

AF:

0.0000612

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:

0.0000374

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000296

AC:

AN:

1451836

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

721468

show subpopulations

Gnomad4 AFR exome

AF:

0.000720

Gnomad4 AMR exome

AF:

0.0000459

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:

0.0000145

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.000138

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000844

Hom.:

Bravo

AF:

0.000257

ESP6500AA

AF:

0.000819

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000663

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 3

Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jan 03, 2018	The observed variant c.10594C>T (p.R3532X) has a minor allele frequency of 0.02% in The 1000 Genomes and 0.01% in ExAC databases. The in silico prediction of the variant is damaging by MutationTaster2. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2021	The DYNC2H1 c.10594C>T; p.Arg3532Ter variant (rs181011657) is reported in the literature in the compound heterozygous state, in individuals with short-rib polydactyly (Badiner 2017, Vora 2017), and bilateral hand and foot polydactyly (Meng 2017). This variant is in ClinVar (Variation ID: 446570) and is listed in the genome Aggregation Database with an overall population frequency of 0.006% (identified on 17 out of 264,854 chromosomes). The c.10594C>T variant creates a termination in the DYNC2H1 protein at codon 3532 in exon 70 which is predicted to result in a truncated or absent protein product. Based on these observations, the p.Arg3532Ter has been classified as pathogenic. Pathogenic variants in DYNC2H1 follow autosomal recessive and digenic recessive (with NEK1 variants) inheritance patterns and are associated with short-rib thoracic dysplasia (SRTD) 3 with or without polydactyly (MIM: 613091). REFERENCES Badiner N et al. Mutations in DYNC2H1, the cytoplasmic dynein 2, heavy chain 1 motor protein gene, cause short-rib polydactyly type I, Saldino-Noonan type. Clin Genet. 2017 Aug;92(2):158-165. Meng L et al. Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management. JAMA Pediatr. 2017 Dec 4;171(12):e173438. Vora NL et al. Prenatal exome sequencing in anomalous fetuses: new opportunities and challenges. Genet Med. 2017 Nov;19(11):1207-1216. -
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:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 2023

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 31345219, 34426522, 31974414, 28973083, 29068549, 28518170, 27925158) -

Jeune thoracic dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

This sequence change creates a premature translational stop signal (p.Arg3532*) 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 (rs181011657, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with short-rib polydactyly type I, Saldino-Noonan type (PMID: 27925158). ClinVar contains an entry for this variant (Variation ID: 446570). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.48

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.87

MutationTaster

Benign

1.0

A;A;D

Vest4

0.90

GERP RS

5.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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