Genetic Variant DYNC2H1:p.Leu1005Phe (chr11-103152204-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001080463.2(DYNC2H1):c.3015A>T(p.Leu1005Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1005L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.834

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12234092).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080463.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC2H1	NM_001080463.2	MANE Plus Clinical	c.3015A>T	p.Leu1005Phe	missense	Exon 21 of 90	NP_001073932.1
	DYNC2H1	NM_001377.3	MANE Select	c.3015A>T	p.Leu1005Phe	missense	Exon 21 of 89	NP_001368.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DYNC2H1	ENST00000650373.2	MANE Plus Clinical	c.3015A>T	p.Leu1005Phe	missense	Exon 21 of 90	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	TSL:1 MANE Select	c.3015A>T	p.Leu1005Phe	missense	Exon 21 of 89	ENSP00000364887.2
DYNC2H1	ENST00000334267.11	TSL:1	c.2205+17785A>T		intron	N/A	ENSP00000334021.7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000406

AC:

AN:

246250

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1457740

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724748

African (AFR)

AF:

0.00

AC:

AN:

33390

American (AMR)

AF:

0.00

AC:

AN:

44442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26058

East Asian (EAS)

AF:

0.00

AC:

AN:

39366

South Asian (SAS)

AF:

0.00

AC:

AN:

84836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110510

Other (OTH)

AF:

0.00

AC:

AN:

60210

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000166

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.094

Eigen_PC

Benign

0.055

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.82

M_CAP

Benign

0.019

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

0.83

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.2

REVEL

Benign

0.067

Sift

Benign

0.035

Sift4G

Uncertain

0.045

Polyphen

0.13

Vest4

0.48

MutPred

0.36

Loss of MoRF binding (P = 0.1325)

MVP

0.43

MPC

0.066

ClinPred

0.20

GERP RS

4.9

Varity_R

0.092

gMVP

0.21

Mutation Taster

=54/46

polymorphism

(source)

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

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