rs199568537

Positions:

chr11-103219963-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001080463.2(DYNC2H1):c.8881G>A(p.Ala2961Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00386 in 1,510,838 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 13 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 8.53

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008848041).

BP6

Variant 11-103219963-G-A is Benign according to our data. Variant chr11-103219963-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103219963-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 13 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.8881G>A	p.Ala2961Thr	missense_variant	56/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3 linkuse as main transcript	c.8881G>A	p.Ala2961Thr	missense_variant	56/89	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.8881G>A	p.Ala2961Thr	missense_variant	56/90		NM_001080463.2	ENSP00000497174	A1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.8881G>A	p.Ala2961Thr	missense_variant	56/89	1	NM_001377.3	ENSP00000364887	P3	Q8NCM8-1
DYNC2H1	ENST00000334267.11 linkuse as main transcript	c.2205+85544G>A		intron_variant		1		ENSP00000334021		Q8NCM8-3

Frequencies

GnomAD3 genomes

AF:

0.00312

AC:

475

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00400

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00472

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00228

AC:

300

AN:

131426

Hom.:

AF XY:

0.00240

AC XY:

172

AN XY:

71802

show subpopulations

Gnomad AFR exome

AF:

0.000880

Gnomad AMR exome

AF:

0.000666

Gnomad ASJ exome

AF:

0.00317

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000847

Gnomad FIN exome

AF:

0.000388

Gnomad NFE exome

AF:

0.00383

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00394

AC:

5353

AN:

1358576

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

2572

AN XY:

671818

show subpopulations

Gnomad4 AFR exome

AF:

0.000595

Gnomad4 AMR exome

AF:

0.00141

Gnomad4 ASJ exome

AF:

0.00333

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000776

Gnomad4 FIN exome

AF:

0.000591

Gnomad4 NFE exome

AF:

0.00462

Gnomad4 OTH exome

AF:

0.00320

GnomAD4 genome

AF:

0.00312

AC:

475

AN:

152262

Hom.:

Cov.:

AF XY:

0.00285

AC XY:

212

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00399

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000943

Gnomad4 NFE

AF:

0.00472

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.00406

Hom.:

Bravo

AF:

0.00336

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000561

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00178

AC:

212

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	DYNC2H1: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2018	This variant is associated with the following publications: (PMID: 24123776) -

Asphyxiating thoracic dystrophy 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 20, 2020	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 05, 2016

- -

Jeune thoracic dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

DYNC2H1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;T;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

.;D;.;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.0088

T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.1

M;M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.1

N;.;.;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.018

D;.;.;D

Sift4G

Benign

0.31

T;.;.;T

Polyphen

0.63

P;P;P;P

Vest4

0.34

MVP

0.77

MPC

0.15

ClinPred

0.020

GERP RS

5.8

Varity_R

0.41

gMVP

0.35

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