rs151156076

Positions:

chr11-103286330-A-G

Variant summary

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

The ENST00000375735.7(DYNC2H1):c.10966A>G(p.Met3656Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,613,738 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 8 hom. )

Consequence

DYNC2H1
ENST00000375735.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.539

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030001998).

BP6

Variant 11-103286330-A-G is Benign according to our data. Variant chr11-103286330-A-G is described in ClinVar as [Benign]. Clinvar id is 459275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00554 (844/152274) while in subpopulation AFR AF= 0.0193 (802/41554). AF 95% confidence interval is 0.0182. There are 6 homozygotes in gnomad4. There are 369 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.10987A>G	p.Met3663Val	missense_variant	75/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3 linkuse as main transcript	c.10966A>G	p.Met3656Val	missense_variant	74/89	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.10987A>G	p.Met3663Val	missense_variant	75/90		NM_001080463.2	ENSP00000497174	A1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.10966A>G	p.Met3656Val	missense_variant	74/89	1	NM_001377.3	ENSP00000364887	P3	Q8NCM8-1
	ENST00000649070.1 linkuse as main transcript	n.690+6686T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00553

AC:

842

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

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:

0.0000882

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00143

AC:

356

AN:

248692

Hom.:

AF XY:

0.00116

AC XY:

157

AN XY:

134872

show subpopulations

Gnomad AFR exome

AF:

0.0207

Gnomad AMR exome

AF:

0.000754

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:

0.0000622

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.000591

AC:

864

AN:

1461464

Hom.:

Cov.:

AF XY:

0.000539

AC XY:

392

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.0213

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.00554

AC:

844

AN:

152274

Hom.:

Cov.:

AF XY:

0.00496

AC XY:

369

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0193

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.00628

ESP6500AA

AF:

0.0204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00189

AC:

229

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 06, 2017

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. -

DYNC2H1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

0.054

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.69

DANN

Benign

0.66

DEOGEN2

Benign

0.043

T;T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.42

.;T;.;T

MetaRNN

Benign

0.0030

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.20

N;N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.1

N;.;.;N

REVEL

Benign

0.050

Sift

Benign

0.35

T;.;.;T

Sift4G

Benign

0.31

T;.;.;T

Polyphen

0.0

B;B;B;B

Vest4

0.15

MVP

0.12

MPC

0.062

ClinPred

0.0014

GERP RS

-3.4

Varity_R

0.097

gMVP

0.22

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