rs963717773

Positions:

chr11-103177665-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_001080463.2(DYNC2H1):c.5984C>T(p.Ala1995Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,000 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.88

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a region_of_interest AAA 2 (size 223) in uniprot entity DYHC2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001080463.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

PP5

Variant 11-103177665-C-T is Pathogenic according to our data. Variant chr11-103177665-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446619.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr11-103177665-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.5984C>T	p.Ala1995Val	missense_variant	38/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3 linkuse as main transcript	c.5984C>T	p.Ala1995Val	missense_variant	38/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2 linkuse as main transcript	c.5984C>T	p.Ala1995Val	missense_variant	38/90		NM_001080463.2	ENSP00000497174	A1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.5984C>T	p.Ala1995Val	missense_variant	38/89	1	NM_001377.3	ENSP00000364887	P3	Q8NCM8-1
DYNC2H1	ENST00000334267.11 linkuse as main transcript	c.2205+43246C>T		intron_variant		1		ENSP00000334021		Q8NCM8-3
DYNC2H1	ENST00000649323.1 linkuse as main transcript	c.*3529C>T		3_prime_UTR_variant, NMD_transcript_variant	36/51			ENSP00000497581

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151894

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:

0.000193

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:

0.00000403

AC:

AN:

248124

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134630

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000559

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:

0.00000753

AC:

AN:

1460988

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726758

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152012

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Jeune thoracic dystrophy

Pathogenic:2Uncertain:1

Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1995 of the DYNC2H1 protein (p.Ala1995Val). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446619). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYNC2H1 protein function. This variant disrupts the p.Ala1995 amino acid residue in DYNC2H1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29068549). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37007936, 29068549, 33777089, 36307859, 26582918, 24077912) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

D;D;.;.

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

.;D;.;D

M_CAP

Benign

0.055

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.8

L;L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.5

D;.;.;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.0020

D;.;.;D

Sift4G

Uncertain

0.0040

D;.;.;D

Polyphen

0.97

D;D;D;D

Vest4

0.84

MutPred

0.75

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MVP

0.75

MPC

0.24

ClinPred

0.94

GERP RS

5.6

Varity_R

0.55

gMVP

0.69

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