rs775426647

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_001080463.2(DYNC2H1):c.6480T>A(p.Asn2160Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,609,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 3.27

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

asphyxiating thoracic dystrophy 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
short rib-polydactyly syndrome, Majewski type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
short rib-polydactyly syndrome, Verma-Naumoff type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DYNC2H1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-103184898-T-A is Pathogenic according to our data. Variant chr11-103184898-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446572.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 link	c.6480T>A	p.Asn2160Lys	missense_variant, splice_region_variant	Exon 41 of 90	ENST00000650373.2	NP_001073932.1	Q8NCM8-2
DYNC2H1	NM_001377.3 link	c.6480T>A	p.Asn2160Lys	missense_variant, splice_region_variant	Exon 41 of 89	ENST00000375735.7	NP_001368.2	Q8NCM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2 link	c.6480T>A	p.Asn2160Lys	missense_variant, splice_region_variant	Exon 41 of 90		NM_001080463.2	ENSP00000497174.1		Q8NCM8-2
DYNC2H1	ENST00000375735.7 link	c.6480T>A	p.Asn2160Lys	missense_variant, splice_region_variant	Exon 41 of 89	1	NM_001377.3	ENSP00000364887.2		Q8NCM8-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000884

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000363

AC:

AN:

248048

AF XY:

0.0000223

show subpopulations

Gnomad AFR exome

AF:

0.0000648

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000712

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000549

AC:

AN:

1458028

Hom.:

Cov.:

AF XY:

0.0000552

AC XY:

AN XY:

725288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33322

American (AMR)

AF:

0.00

AC:

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25966

East Asian (EAS)

AF:

0.00

AC:

AN:

39524

South Asian (SAS)

AF:

0.00

AC:

AN:

86034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0000721

AC:

AN:

1109370

Other (OTH)

AF:

0.00

AC:

AN:

60156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151892

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000884

AC:

AN:

67874

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 3

Pathogenic:3Uncertain:1

Apr 27, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1, PM2, PM3 -

May 15, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Jeune thoracic dystrophy

Uncertain:1

Jun 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 2160 of the DYNC2H1 protein (p.Asn2160Lys). This variant is present in population databases (rs775426647, gnomAD 0.008%). This missense change has been observed in individual(s) with DYNC2H1-related conditions (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446572). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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

Benign

0.14

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.17

T;T;.;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

.;D;.;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;M;M;M

PhyloP100

3.3

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.8

D;.;.;D

REVEL

Benign

0.15

Sift

Benign

0.28

T;.;.;T

Sift4G

Benign

0.90

T;.;.;T

Polyphen

0.0

B;B;B;B

Vest4

0.82

MutPred

0.66

Gain of ubiquitination at N2160 (P = 0.0131);Gain of ubiquitination at N2160 (P = 0.0131);Gain of ubiquitination at N2160 (P = 0.0131);Gain of ubiquitination at N2160 (P = 0.0131);

MVP

0.16

MPC

0.076

ClinPred

0.16

GERP RS

4.1

Varity_R

0.28

gMVP

0.56

Mutation Taster

=13/87

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over