Variant rs764468030 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_001080463.2(DYNC2H1):c.8003T>G(p.Val2668Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,250 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 6.20

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001080463.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.899

PP5

Variant 11-103199391-T-G is Pathogenic according to our data. Variant chr11-103199391-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 558739.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.8003T>G	p.Val2668Gly	missense_variant	49/90	ENST00000650373.2
DYNC2H1	NM_001377.3 linkuse as main transcript	c.8003T>G	p.Val2668Gly	missense_variant	49/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2 linkuse as main transcript	c.8003T>G	p.Val2668Gly	missense_variant	49/90		NM_001080463.2	A1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.8003T>G	p.Val2668Gly	missense_variant	49/89	1	NM_001377.3	P3	Q8NCM8-1
DYNC2H1	ENST00000334267.11 linkuse as main transcript	c.2205+64972T>G		intron_variant		1			Q8NCM8-3
DYNC2H1	ENST00000649323.1 linkuse as main transcript	c.*5527T>G		3_prime_UTR_variant, NMD_transcript_variant	47/51

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248298

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134698

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460250

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726406

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Nov 21, 2014

- -

Jeune thoracic dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Rare Disease Group, Clinical Genetics, Karolinska Institutet

May 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;D;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

.;T;.;T

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.8

M;M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.3

D;.;.;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0010

D;.;.;D

Sift4G

Uncertain

0.0020

D;.;.;D

Polyphen

0.85

P;P;P;P

Vest4

0.60

MutPred

0.76

Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);

MVP

0.56

MPC

0.26

ClinPred

0.98

GERP RS

6.1

Varity_R

0.88

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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