rs775426647

Positions:

chr11-103184898-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5

The NM_001080463.2(DYNC2H1):c.6480T>A(p.Asn2160Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,609,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

DYNC2H1
NM_001080463.2 missense, splice_region

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.27

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.

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;

PP5

Variant 11-103184898-T-A is Pathogenic according to our data. Variant chr11-103184898-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446572.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2 linkuse as main transcript	c.6480T>A	p.Asn2160Lys	missense_variant, splice_region_variant	41/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3 linkuse as main transcript	c.6480T>A	p.Asn2160Lys	missense_variant, splice_region_variant	41/89	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.6480T>A	p.Asn2160Lys	missense_variant, splice_region_variant	41/90		NM_001080463.2	ENSP00000497174	A1	Q8NCM8-2
DYNC2H1	ENST00000375735.7 linkuse as main transcript	c.6480T>A	p.Asn2160Lys	missense_variant, splice_region_variant	41/89	1	NM_001377.3	ENSP00000364887	P3	Q8NCM8-1
DYNC2H1	ENST00000334267.11 linkuse as main transcript	c.2205+50479T>A		intron_variant		1		ENSP00000334021		Q8NCM8-3
DYNC2H1	ENST00000649323.1 linkuse as main transcript	c.*4025T>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	39/51			ENSP00000497581

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151892

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000884

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000363

AC:

AN:

248048

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134560

show subpopulations

Gnomad AFR exome

AF:

0.0000648

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:

0.0000712

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000549

AC:

AN:

1458028

Hom.:

Cov.:

AF XY:

0.0000552

AC XY:

AN XY:

725288

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:

0.0000721

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151892

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74186

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000884

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Asphyxiating thoracic dystrophy 3

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 27, 2022	PM1, PM2, PM3 -
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	- -

Jeune thoracic dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 09, 2022

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 2160 of the DYNC2H1 protein (p.Asn2160Lys). This variant is present in population databases (rs775426647, gnomAD 0.008%). This missense change has been observed in individual(s) with DYNC2H1-related conditions (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446572). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

Benign

0.14

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.17

T;T;.;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

.;D;.;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.8

D;.;.;D

REVEL

Benign

0.15

Sift

Benign

0.28

T;.;.;T

Sift4G

Benign

0.90

T;.;.;T

Polyphen

0.0

B;B;B;B

Vest4

0.82

MutPred

0.66

Gain of ubiquitination at N2160 (P = 0.0131);Gain of ubiquitination at N2160 (P = 0.0131);Gain of ubiquitination at N2160 (P = 0.0131);Gain of ubiquitination at N2160 (P = 0.0131);

MVP

0.16

MPC

0.076

ClinPred

0.16

GERP RS

4.1

Varity_R

0.28

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: 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