Genetic Variant DYNC2H1:p.Lys1413Ile (chr11-103158787-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001377.3(DYNC2H1):c.4238A>T(p.Lys1413Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1413R) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DYNC2H1
NM_001377.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.90

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), Ambry Genetics, Orphanet, G2P, ClinGen
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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.4238A>T	p.Lys1413Ile	missense	Exon 27 of 90	NP_001073932.1	Q8NCM8-2
	DYNC2H1	NM_001377.3	MANE Select	c.4238A>T	p.Lys1413Ile	missense	Exon 27 of 89	NP_001368.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.4238A>T	p.Lys1413Ile	missense	Exon 27 of 90	ENSP00000497174.1	Q8NCM8-2
DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.4238A>T	p.Lys1413Ile	missense	Exon 27 of 89	ENSP00000364887.2	Q8NCM8-1
DYNC2H1	ENST00000334267.11	TSL:1	c.2205+24368A>T		intron	N/A	ENSP00000334021.7	Q8NCM8-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1327964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

655746

African (AFR)

AF:

0.00

AC:

AN:

29384

American (AMR)

AF:

0.00

AC:

AN:

30188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24186

East Asian (EAS)

AF:

0.00

AC:

AN:

34896

South Asian (SAS)

AF:

0.00

AC:

AN:

70238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48794

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4982

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1029828

Other (OTH)

AF:

0.00

AC:

AN:

55468

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

4.4

PhyloP100

3.9

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.62

MutPred

0.62

Loss of ubiquitination at K1413 (P = 0.0174)

MVP

0.81

MPC

0.50

ClinPred

0.99

GERP RS

5.8

Varity_R

0.88

gMVP

0.69

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over