rs549891589

Positions:

chr11-103321048-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001377.3(DYNC2H1):c.11745G>T(p.Trp3915Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,609,516 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

DYNC2H1
NM_001377.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.36

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.11766G>T	p.Trp3922Cys	missense_variant	82/90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 linkuse as main transcript	c.11745G>T	p.Trp3915Cys	missense_variant	81/89	ENST00000375735.7	NP_001368.2	Q8NCM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DYNC2H1	ENST00000650373.2 linkuse as main transcript	c.11766G>T	p.Trp3922Cys	missense_variant	82/90		NM_001080463.2	ENSP00000497174.1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.11745G>T	p.Trp3915Cys	missense_variant	81/89	1	NM_001377.3	ENSP00000364887.2	Q8NCM8-1
DYNC2H1	ENST00000334267.11 linkuse as main transcript	c.2206-114895G>T		intron_variant		1		ENSP00000334021.7	Q8NCM8-3
DYNC2H1	ENST00000528670.5 linkuse as main transcript	n.924G>T		non_coding_transcript_exon_variant	9/17	5		ENSP00000433451.1	H0YDE0

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000448

AC:

AN:

245554

Hom.:

AF XY:

0.0000301

AC XY:

AN XY:

133108

show subpopulations

Gnomad AFR exome

AF:

0.000723

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000686

AC:

AN:

1457440

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724642

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000227

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.0000580

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Jeune thoracic dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 3922 of the DYNC2H1 protein (p.Trp3922Cys). This variant is present in population databases (rs549891589, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with DYNC2H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 459276). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYNC2H1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.0022

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D;.;D

M_CAP

Benign

0.082

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Benign

-0.76

MutationAssessor

Pathogenic

3.2

M;M;.;.

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-12

D;.;.;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

D;.;.;D

Sift4G

Pathogenic

0.0010

D;.;.;D

Polyphen

1.0

D;D;D;D

Vest4

0.86

MutPred

0.83

Loss of ubiquitination at K3911 (P = 0.1351);Loss of ubiquitination at K3911 (P = 0.1351);.;.;

MVP

0.56

MPC

0.47

ClinPred

0.94

GERP RS

5.8

Varity_R

0.98

gMVP

0.93

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