rs72989738

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001377.3(DYNC2H1):c.4728C>G(p.Asn1576Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0294 in 1,532,380 control chromosomes in the GnomAD database, including 804 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 59 hom., cov: 32)

Exomes 𝑓: 0.030 ( 745 hom. )

Consequence

DYNC2H1
NM_001377.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.193

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019398034).

BP6

Variant 11-103166014-C-G is Benign according to our data. Variant chr11-103166014-C-G is described in ClinVar as [Benign]. Clinvar id is 379420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103166014-C-G is described in Lovd as [Likely_benign]. Variant chr11-103166014-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0233 (3541/152226) while in subpopulation NFE AF= 0.0347 (2362/67994). AF 95% confidence interval is 0.0336. There are 59 homozygotes in gnomad4. There are 1695 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 59 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.4728C>G	p.Asn1576Lys	missense_variant	31/90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 linkuse as main transcript	c.4728C>G	p.Asn1576Lys	missense_variant	31/89	ENST00000375735.7	NP_001368.2	Q8NCM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2 linkuse as main transcript	c.4728C>G	p.Asn1576Lys	missense_variant	31/90		NM_001080463.2	ENSP00000497174.1		Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.4728C>G	p.Asn1576Lys	missense_variant	31/89	1	NM_001377.3	ENSP00000364887.2		Q8NCM8-1

Frequencies

GnomAD3 genomes

AF:

0.0233

AC:

3542

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00546

Gnomad AMI

AF:

0.0647

Gnomad AMR

AF:

0.0303

Gnomad ASJ

AF:

0.0429

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0347

Gnomad OTH

AF:

0.0435

GnomAD3 exomes

AF:

0.0212

AC:

3057

AN:

144372

Hom.:

AF XY:

0.0209

AC XY:

1592

AN XY:

76196

show subpopulations

Gnomad AFR exome

AF:

0.00527

Gnomad AMR exome

AF:

0.0183

Gnomad ASJ exome

AF:

0.0411

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00450

Gnomad FIN exome

AF:

0.0161

Gnomad NFE exome

AF:

0.0318

Gnomad OTH exome

AF:

0.0334

GnomAD4 exome

AF:

0.0301

AC:

41525

AN:

1380154

Hom.:

745

Cov.:

AF XY:

0.0293

AC XY:

19940

AN XY:

679476

show subpopulations

Gnomad4 AFR exome

AF:

0.00532

Gnomad4 AMR exome

AF:

0.0216

Gnomad4 ASJ exome

AF:

0.0413

Gnomad4 EAS exome

AF:

0.0000861

Gnomad4 SAS exome

AF:

0.00531

Gnomad4 FIN exome

AF:

0.0184

Gnomad4 NFE exome

AF:

0.0340

Gnomad4 OTH exome

AF:

0.0295

GnomAD4 genome

AF:

0.0233

AC:

3541

AN:

152226

Hom.:

Cov.:

AF XY:

0.0228

AC XY:

1695

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00544

Gnomad4 AMR

AF:

0.0302

Gnomad4 ASJ

AF:

0.0429

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00414

Gnomad4 FIN

AF:

0.0150

Gnomad4 NFE

AF:

0.0347

Gnomad4 OTH

AF:

0.0435

Alfa

AF:

0.0295

Hom.:

Bravo

AF:

0.0243

TwinsUK

AF:

0.0307

AC:

114

ALSPAC

AF:

0.0371

AC:

143

ESP6500AA

AF:

0.00779

AC:

ESP6500EA

AF:

0.0284

AC:

208

ExAC

AF:

0.00976

AC:

561

Asia WGS

AF:

0.00492

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, gene associated with Jeune syndrome -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Asphyxiating thoracic dystrophy 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
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. -

Jeune thoracic dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.72

CADD

Benign

3.7

DANN

Uncertain

0.98

DEOGEN2

Benign

0.076

T;T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.81

.;T;.;T

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L;L;L

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.7

N;.;.;N

REVEL

Benign

0.054

Sift

Benign

0.28

T;.;.;T

Sift4G

Benign

0.12

T;.;.;T

Polyphen

0.0

B;B;B;B

Vest4

0.32

MutPred

0.37

Gain of ubiquitination at N1576 (P = 0.0114);Gain of ubiquitination at N1576 (P = 0.0114);Gain of ubiquitination at N1576 (P = 0.0114);Gain of ubiquitination at N1576 (P = 0.0114);

MPC

0.070

ClinPred

0.0032

GERP RS

-2.1

Varity_R

0.070

gMVP

0.15

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