Variant 11-103209933-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000375735.7(DYNC2H1):c.8512C>T(p.Arg2838Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,337,604 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: not found (cov: 32)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

DYNC2H1
ENST00000375735.7 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.784

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:

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 11-103209933-C-T is Pathogenic according to our data. Variant chr11-103209933-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.8512C>T	p.Arg2838Ter	stop_gained	53/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3 linkuse as main transcript	c.8512C>T	p.Arg2838Ter	stop_gained	53/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2 linkuse as main transcript	c.8512C>T	p.Arg2838Ter	stop_gained	53/90		NM_001080463.2	ENSP00000497174	A1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.8512C>T	p.Arg2838Ter	stop_gained	53/89	1	NM_001377.3	ENSP00000364887	P3	Q8NCM8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000170

AC:

AN:

117552

Hom.:

AF XY:

0.0000159

AC XY:

AN XY:

62792

show subpopulations

Gnomad AFR exome

AF:

0.000173

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:

0.0000207

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000374

AC:

AN:

1337604

Hom.:

Cov.:

AF XY:

0.00000304

AC XY:

AN XY:

658412

show subpopulations

Gnomad4 AFR exome

AF:

0.0000351

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:

0.00000381

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 3

Pathogenic:4

Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 23, 2021	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -

Jeune thoracic dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 29, 2023

This sequence change creates a premature translational stop signal (p.Arg2838*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6508). This premature translational stop signal has been observed in individual(s) with DYNC2H1-related conditions (PMID: 19361615). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. -

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

0.28

Eigen_PC

Benign

0.057

FATHMM_MKL

Benign

0.35

MutationTaster

Benign

1.0

A;A;A

Vest4

0.68

GERP RS

0.69

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