chr14-102041719-C-A

Position:

chr14-102041719-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001376.5(DYNC1H1):c.12087C>A(p.His4029Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0728 in 1,614,016 control chromosomes in the GnomAD database, including 6,314 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1814 hom., cov: 32)

Exomes 𝑓: 0.068 ( 4500 hom. )

Consequence

DYNC1H1
NM_001376.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.457

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DYNC1H1. . Gene score misZ 10.967 (greater than the threshold 3.09). Trascript score misZ 16.053 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.0016406178).

BP6

Variant 14-102041719-C-A is Benign according to our data. Variant chr14-102041719-C-A is described in ClinVar as [Benign]. Clinvar id is 128928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-102041719-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC1H1	NM_001376.5 linkuse as main transcript	c.12087C>A	p.His4029Gln	missense_variant	65/78	ENST00000360184.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC1H1	ENST00000360184.10 linkuse as main transcript	c.12087C>A	p.His4029Gln	missense_variant	65/78	1	NM_001376.5	P1
	ENST00000553701.1 linkuse as main transcript	n.347-4950G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.121

AC:

18430

AN:

152120

Hom.:

1815

Cov.:

show subpopulations

Gnomad AFR

AF:

0.270

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.0649

Gnomad ASJ

AF:

0.0527

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0230

Gnomad FIN

AF:

0.104

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0667

Gnomad OTH

AF:

0.113

GnomAD3 exomes

AF:

0.0693

AC:

17413

AN:

251132

Hom.:

1069

AF XY:

0.0640

AC XY:

8692

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.277

Gnomad AMR exome

AF:

0.0425

Gnomad ASJ exome

AF:

0.0429

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0266

Gnomad FIN exome

AF:

0.0917

Gnomad NFE exome

AF:

0.0688

Gnomad OTH exome

AF:

0.0662

GnomAD4 exome

AF:

0.0678

AC:

99066

AN:

1461778

Hom.:

4500

Cov.:

AF XY:

0.0658

AC XY:

47814

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.281

Gnomad4 AMR exome

AF:

0.0455

Gnomad4 ASJ exome

AF:

0.0434

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0278

Gnomad4 FIN exome

AF:

0.0932

Gnomad4 NFE exome

AF:

0.0669

Gnomad4 OTH exome

AF:

0.0731

GnomAD4 genome

AF:

0.121

AC:

18455

AN:

152238

Hom.:

1814

Cov.:

AF XY:

0.118

AC XY:

8790

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.270

Gnomad4 AMR

AF:

0.0647

Gnomad4 ASJ

AF:

0.0527

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0224

Gnomad4 FIN

AF:

0.104

Gnomad4 NFE

AF:

0.0667

Gnomad4 OTH

AF:

0.112

Alfa

AF:

0.0743

Hom.:

1100

Bravo

AF:

0.126

TwinsUK

AF:

0.0585

AC:

217

ALSPAC

AF:

0.0675

AC:

260

ESP6500AA

AF:

0.272

AC:

1199

ESP6500EA

AF:

0.0621

AC:

534

ExAC

AF:

0.0740

AC:

8982

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0620

EpiControl

AF:

0.0672

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Charcot-Marie-Tooth disease axonal type 2O

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal dominant cerebellar ataxia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.084

T;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.55

N;.

MutationTaster

Benign

0.00065

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.2

N;.

REVEL

Benign

0.12

Sift

Benign

0.66

T;.

Polyphen

0.0010

B;.

Vest4

0.17

MutPred

0.26

Gain of helix (P = 0.132);.;

MPC

0.94

ClinPred

0.010

GERP RS

4.6

Varity_R

0.18

gMVP

0.64

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