rs878854166

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_001080463.2(DYNC2H1):c.5114T>C(p.Leu1705Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000249 in 1,606,128 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 0.000013 ( 0 hom., 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: 5.09

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.848

PP5

Variant 11-103170253-T-C is Pathogenic according to our data. Variant chr11-103170253-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238271.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.5114T>C	p.Leu1705Pro	missense_variant	33/90	ENST00000650373.2
DYNC2H1	NM_001377.3 linkuse as main transcript	c.5114T>C	p.Leu1705Pro	missense_variant	33/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2 linkuse as main transcript	c.5114T>C	p.Leu1705Pro	missense_variant	33/90		NM_001080463.2	A1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.5114T>C	p.Leu1705Pro	missense_variant	33/89	1	NM_001377.3	P3	Q8NCM8-1
DYNC2H1	ENST00000334267.11 linkuse as main transcript	c.2205+35834T>C		intron_variant		1			Q8NCM8-3
DYNC2H1	ENST00000649323.1 linkuse as main transcript	c.*2659T>C		3_prime_UTR_variant, NMD_transcript_variant	31/51

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.00000420

AC:

AN:

238174

Hom.:

AF XY:

0.00

AC XY:

AN XY:

128998

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000312

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:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1453896

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722636

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000231

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

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:

0.00

Bravo

AF:

0.00000756

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

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2017

The L1705P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge; however, it has been observed at GeneDx in trans with another expected pathogenic variant in two affected siblings with clinical features of a DYNC2H1-related disorder. In addition, it has also been observed in two fetal demise siblings in the presence of another expected pathogenic variant in trans. The L1705P variant is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). L1705P is a semi- conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, this variant is interpreted as likely pathogenic. -

Jeune thoracic dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 05, 2022

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1705 of the DYNC2H1 protein (p.Leu1705Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of short rib thoracic dysplasia (Aza 2017, abstract 194; http://www.endocrinologiapediatrica.org/revistas/P1-E22/P1-E22-S1043-A411.pdf). ClinVar contains an entry for this variant (Variation ID: 238271). 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) performed at Invitae indicates that this missense variant is not expected to disrupt DYNC2H1 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;T;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.85

.;T;.;T

M_CAP

Benign

0.064

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.9

M;M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.2

D;.;.;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.019

D;.;.;D

Sift4G

Uncertain

0.016

D;.;.;D

Polyphen

1.0

D;D;D;D

Vest4

0.87

MutPred

0.71

Gain of disorder (P = 0.0302);Gain of disorder (P = 0.0302);Gain of disorder (P = 0.0302);Gain of disorder (P = 0.0302);

MVP

0.63

MPC

0.45

ClinPred

0.97

GERP RS

5.5

Varity_R

0.95

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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