rs552436294

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_001080463.2(DYNC2H1):c.5983G>A(p.Ala1995Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000384 in 1,613,374 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1995V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.61

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a region_of_interest AAA 2 (size 223) in uniprot entity DYHC2_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in NM_001080463.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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: {Pathogenic=1, Uncertain_significance=1}.

PP5

Variant 11-103177664-G-A is Pathogenic according to our data. Variant chr11-103177664-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 419236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.5983G>A	p.Ala1995Thr	missense_variant	38/90	ENST00000650373.2
DYNC2H1	NM_001377.3 linkuse as main transcript	c.5983G>A	p.Ala1995Thr	missense_variant	38/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2 linkuse as main transcript	c.5983G>A	p.Ala1995Thr	missense_variant	38/90		NM_001080463.2	A1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.5983G>A	p.Ala1995Thr	missense_variant	38/89	1	NM_001377.3	P3	Q8NCM8-1
DYNC2H1	ENST00000334267.11 linkuse as main transcript	c.2205+43245G>A		intron_variant		1			Q8NCM8-3
DYNC2H1	ENST00000649323.1 linkuse as main transcript	c.*3528G>A		3_prime_UTR_variant, NMD_transcript_variant	36/51

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00112

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248298

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134706

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000877

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:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461184

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726856

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

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:

0.0000315

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000118

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Bravo

AF:

0.000200

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Jeune thoracic dystrophy

Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1995 of the DYNC2H1 protein (p.Ala1995Thr). This variant is present in population databases (rs552436294, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of short-rib polydactyly syndrome (PMID: 29068549, 32494556). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 419236). 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. For these reasons, this variant has been classified as Pathogenic. -

Asphyxiating thoracic dystrophy 3

Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 21, 2022	- -

DYNC2H1-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2023

The DYNC2H1 c.5983G>A variant is predicted to result in the amino acid substitution p.Ala1995Thr. This variant was reported in at least four unrelated cases of short rib-polydactyly syndrome, type 3 (Table S2, Zhang et al. 2018. PubMed ID: 29068549; Geng et al. 2020. PubMed ID: 32494556). A different substitution affecting the same amino acid (p.Ala1995Val) was also reported in patients with short rib-polydactyly syndrome (Table S2, Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.0088% of alleles in individuals of Latino descent in gnomAD. At PreventionGenetics, we have observed this variant in an individual tested for short rib skeletal dysplasia. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2023

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31589614, 29068549, 32494556) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.19

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

D;D;.;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.45

T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.7

L;L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.6

D;.;.;D

REVEL

Benign

0.29

Sift

Uncertain

0.0030

D;.;.;D

Sift4G

Uncertain

0.0050

D;.;.;D

Polyphen

0.85

P;P;P;P

Vest4

0.78

MutPred

0.70

Gain of phosphorylation at A1995 (P = 0.0783);Gain of phosphorylation at A1995 (P = 0.0783);Gain of phosphorylation at A1995 (P = 0.0783);Gain of phosphorylation at A1995 (P = 0.0783);

MVP

0.74

MPC

0.25

ClinPred

0.78

GERP RS

3.6

Varity_R

0.41

gMVP

0.60

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