rs112718117

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001080463.2(DYNC2H1):c.195+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00984 in 1,609,006 control chromosomes in the GnomAD database, including 160 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.012 ( 23 hom., cov: 32)

Exomes 𝑓: 0.0096 ( 137 hom. )

Consequence

DYNC2H1
NM_001080463.2 splice_region, intron

Scores

Splicing: ADA: 0.00003429

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -1.48

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 11-103109776-T-C is Benign according to our data. Variant chr11-103109776-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 301996.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}. Variant chr11-103109776-T-C is described in Lovd as [Likely_benign]. Variant chr11-103109776-T-C is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.195+7T>C		splice_region_variant, intron_variant		ENST00000650373.2
DYNC2H1	NM_001377.3 linkuse as main transcript	c.195+7T>C		splice_region_variant, intron_variant		ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.195+7T>C		splice_region_variant, intron_variant		1	NM_001377.3	P3	Q8NCM8-1
DYNC2H1	ENST00000650373.2 linkuse as main transcript	c.195+7T>C		splice_region_variant, intron_variant			NM_001080463.2	A1	Q8NCM8-2

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1811

AN:

151712

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0138

Gnomad ASJ

AF:

0.0557

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00285

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.0192

GnomAD3 exomes

AF:

0.0106

AC:

2609

AN:

245900

Hom.:

AF XY:

0.0104

AC XY:

1393

AN XY:

133312

show subpopulations

Gnomad AFR exome

AF:

0.0125

Gnomad AMR exome

AF:

0.0105

Gnomad ASJ exome

AF:

0.0484

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00360

Gnomad FIN exome

AF:

0.00357

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.0196

GnomAD4 exome

AF:

0.00963

AC:

14033

AN:

1457176

Hom.:

137

Cov.:

AF XY:

0.00978

AC XY:

7085

AN XY:

724270

show subpopulations

Gnomad4 AFR exome

AF:

0.0137

Gnomad4 AMR exome

AF:

0.0107

Gnomad4 ASJ exome

AF:

0.0523

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00375

Gnomad4 FIN exome

AF:

0.00455

Gnomad4 NFE exome

AF:

0.00895

Gnomad4 OTH exome

AF:

0.0157

GnomAD4 genome

AF:

0.0119

AC:

1805

AN:

151830

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

850

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.0131

Gnomad4 AMR

AF:

0.0137

Gnomad4 ASJ

AF:

0.0557

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00291

Gnomad4 FIN

AF:

0.00285

Gnomad4 NFE

AF:

0.0111

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0127

Hom.:

Bravo

AF:

0.0130

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DYNC2H1: BP4, BS1, BS2 -

Asphyxiating thoracic dystrophy 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Short rib-polydactyly syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Jeune thoracic dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

Cadd

Benign

2.4

Dann

Benign

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000034

dbscSNV1_RF

Benign

0.0

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