chr2-74371596-T-C

Position:

chr2-74371596-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004082.5(DCTN1):c.586A>G(p.Ile196Val) variant causes a missense change. The variant allele was found at a frequency of 0.00614 in 1,588,362 control chromosomes in the GnomAD database, including 40 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0045 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 37 hom. )

Consequence

DCTN1
NM_004082.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 4.50

Variant links:

Genes affected

DCTN1 (HGNC:2711): (dynactin subunit 1) This gene encodes the largest subunit of dynactin, a macromolecular complex consisting of 10 subunits ranging in size from 22 to 150 kD. Dynactin binds to both microtubules and cytoplasmic dynein. Dynactin is involved in a diverse array of cellular functions, including ER-to-Golgi transport, the centripetal movement of lysosomes and endosomes, spindle formation, chromosome movement, nuclear positioning, and axonogenesis. This subunit interacts with dynein intermediate chain by its domains directly binding to dynein and binds to microtubules via a highly conserved glycine-rich cytoskeleton-associated protein (CAP-Gly) domain in its N-terminus. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. Mutations in this gene cause distal hereditary motor neuronopathy type VIIB (HMN7B) which is also known as distal spinal and bulbar muscular atrophy (dSBMA). [provided by RefSeq, Oct 2008]

DCTN1 links:

DCTN1 (HGNC:):

DCTN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054398477).

BP6

Variant 2-74371596-T-C is Benign according to our data. Variant chr2-74371596-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 337096.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=6}. Variant chr2-74371596-T-C is described in Lovd as [Benign]. Variant chr2-74371596-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00448 (681/151948) while in subpopulation NFE AF= 0.00671 (456/67930). AF 95% confidence interval is 0.0062. There are 3 homozygotes in gnomad4. There are 276 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 681 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCTN1	NM_004082.5 linkuse as main transcript	c.586A>G	p.Ile196Val	missense_variant	8/32	ENST00000628224.3	NP_004073.2	Q14203-1Q6MZZ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCTN1	ENST00000628224.3 linkuse as main transcript	c.586A>G	p.Ile196Val	missense_variant	8/32	5	NM_004082.5	ENSP00000487279.2		Q14203-1E7EX90

Frequencies

GnomAD3 genomes

AF:

0.00449

AC:

681

AN:

151830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00119

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.00328

Gnomad ASJ

AF:

0.0231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00274

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00671

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00460

AC:

948

AN:

205926

Hom.:

AF XY:

0.00438

AC XY:

483

AN XY:

110166

show subpopulations

Gnomad AFR exome

AF:

0.000630

Gnomad AMR exome

AF:

0.00391

Gnomad ASJ exome

AF:

0.0200

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00103

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00615

Gnomad OTH exome

AF:

0.00574

GnomAD4 exome

AF:

0.00632

AC:

9075

AN:

1436414

Hom.:

Cov.:

AF XY:

0.00624

AC XY:

4444

AN XY:

711960

show subpopulations

Gnomad4 AFR exome

AF:

0.000663

Gnomad4 AMR exome

AF:

0.00449

Gnomad4 ASJ exome

AF:

0.0202

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000899

Gnomad4 FIN exome

AF:

0.00141

Gnomad4 NFE exome

AF:

0.00703

Gnomad4 OTH exome

AF:

0.00767

GnomAD4 genome

AF:

0.00448

AC:

681

AN:

151948

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

276

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.0231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00105

Gnomad4 FIN

AF:

0.00274

Gnomad4 NFE

AF:

0.00671

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00686

Hom.:

Bravo

AF:

0.00483

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00768

AC:

ExAC

AF:

0.00356

AC:

430

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2018	This variant is associated with the following publications: (PMID: 23143281, 25382069) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	DCTN1: BS2 -

Perry syndrome

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 10, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Amyotrophic lateral sclerosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

UM ALS/MND Lab, University Of Malta

Sep 09, 2020

- -

Neuronopathy, distal hereditary motor, type 7B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Neuronopathy, distal hereditary motor, type 7B;C1862939:Amyotrophic lateral sclerosis type 1;C1868594:Perry syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.065

T;.;T;.;.;.;T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

0.044

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

T;T;T;T;T;T;.;T

MetaRNN

Benign

0.0054

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.76

N;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.20

N;N;.;.;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.54

T;T;.;.;T;T;T;T

Sift4G

Benign

0.81

T;T;T;T;T;T;T;T

Polyphen

0.0010

B;.;.;B;.;.;.;.

Vest4

0.32

MVP

0.75

MPC

0.49

ClinPred

0.0075

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.024

gMVP

0.16

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