rs768668529

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4BP6BS1BS2

The NM_001376.5(DYNC1H1):c.10743A>C(p.Lys3581Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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: 0.000015 ( 0 hom. )

Consequence

DYNC1H1
NM_001376.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.218

Variant links:

Genes affected

DYNC1H1 (HGNC:2961): (dynein cytoplasmic 1 heavy chain 1) Dyneins are a group of microtubule-activated ATPases that function as molecular motors. They are divided into two subgroups of axonemal and cytoplasmic dyneins. The cytoplasmic dyneins function in intracellular motility, including retrograde axonal transport, protein sorting, organelle movement, and spindle dynamics. Molecules of conventional cytoplasmic dynein are comprised of 2 heavy chain polypeptides and a number of intermediate and light chains.This gene encodes a member of the cytoplasmic dynein heavy chain family. [provided by RefSeq, Oct 2008]

DYNC1H1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP2

Missense variant in the DYNC1H1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 122 curated pathogenic missense variants (we use a threshold of 10). The gene has 287 curated benign missense variants. Gene score misZ: 10.967 (above the threshold of 3.09). Trascript score misZ: 16.053 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant non-syndromic intellectual disability, neuronopathy, distal hereditary motor, intellectual disability, autosomal dominant 13, autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures, Charcot-Marie-Tooth disease axonal type 2O.

BP4

Computational evidence support a benign effect (MetaRNN=0.28877872).

BP6

Variant 14-102034441-A-C is Benign according to our data. Variant chr14-102034441-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 246514.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000151 (22/1460596) while in subpopulation NFE AF= 0.0000198 (22/1112006). AF 95% confidence interval is 0.000013. There are 0 homozygotes in gnomad4_exome. There are 9 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1H1	NM_001376.5 link	c.10743A>C	p.Lys3581Asn	missense_variant	Exon 56 of 78	ENST00000360184.10	NP_001367.2	Q14204

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10 link	c.10743A>C	p.Lys3581Asn	missense_variant	Exon 56 of 78	1	NM_001376.5	ENSP00000348965.4		Q14204

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152148

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251462

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135906

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1460596

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726612

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:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 24, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K3581N variant (also known as c.10743A>C), located in coding exon 56 of the DYNC1H1 gene, results from an A to C substitution at nucleotide position 10743. The lysine at codon 3581 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Mar 31, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The K3581N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K3581N variant 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. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with DYNC1H1-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Charcot-Marie-Tooth disease axonal type 2O

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.70

D;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.81

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.067

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.3

L;.

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.4

D;.

REVEL

Uncertain

0.33

Sift

Benign

0.036

D;.

Polyphen

0.96

D;.

Vest4

0.81

MutPred

0.63

Loss of ubiquitination at K3581 (P = 0.0546);.;

MVP

0.52

MPC

1.9

ClinPred

0.87

GERP RS

-9.0

Varity_R

0.66

gMVP

0.98

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