14-102015282-C-T

Position:

chr14-102015282-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001376.5(DYNC1H1):c.7192C>T(p.Arg2398Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00021 in 1,614,040 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

DYNC1H1
NM_001376.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 3.64

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 -10 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=0.12651789).

BP6

Variant 14-102015282-C-T is Benign according to our data. Variant chr14-102015282-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285546.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000283 (43/152180) while in subpopulation AMR AF= 0.00111 (17/15280). AF 95% confidence interval is 0.000708. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC1H1	NM_001376.5 linkuse as main transcript	c.7192C>T	p.Arg2398Cys	missense_variant	35/78	ENST00000360184.10	NP_001367.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10 linkuse as main transcript	c.7192C>T	p.Arg2398Cys	missense_variant	35/78	1	NM_001376.5	ENSP00000348965	P1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000362

AC:

AN:

251118

Hom.:

AF XY:

0.000353

AC XY:

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000202

AC:

296

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000191

AC XY:

139

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00150

Gnomad4 NFE exome

AF:

0.000172

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000283

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74336

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:

0.000377

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000117

Hom.:

Bravo

AF:

0.000234

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000387

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2020	This variant is associated with the following publications: (PMID: 26100331, 23891399) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	DYNC1H1: PP2, BS1 -

Charcot-Marie-Tooth disease axonal type 2O

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 30, 2016

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2020

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

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.011

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.15

Sift

Benign

0.050

Polyphen

0.98

Vest4

0.69

MVP

0.50

MPC

2.2

ClinPred

0.30

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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