2-74367083-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_004082.5(DCTN1):c.2278A>G(p.Met760Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000867 in 1,614,076 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 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

DCTN1
NM_004082.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 5.63

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15262413).

BP6

Variant 2-74367083-T-C is Benign according to our data. Variant chr2-74367083-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 337081.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000657 (10/152190) while in subpopulation AMR AF= 0.000131 (2/15274). AF 95% confidence interval is 0.0000584. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCTN1	NM_004082.5 link	c.2278A>G	p.Met760Val	missense_variant	Exon 20 of 32	ENST00000628224.3	NP_004073.2	Q14203-1Q6MZZ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCTN1	ENST00000628224.3 link	c.2278A>G	p.Met760Val	missense_variant	Exon 20 of 32	5	NM_004082.5	ENSP00000487279.2		Q14203-1E7EX90

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000143

AC:

AN:

251420

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000781

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:

0.0000791

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000889

AC:

130

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000890

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

DCTN1-related disorder

Uncertain:1

Mar 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DCTN1 c.2278A>G variant is predicted to result in the amino acid substitution p.Met760Val. This variant has been reported in multiple individuals with hereditary motor neuropathy (Table S3 - Antoniadi et al. 2015. PubMed ID: 26392352). However, this variant is reported in 0.076% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-74594210-T-C). Functional studies suggest this variant may not alter protein function (Stockmann et al. 2012. PubMed ID: 23143281). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Aug 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Mar 30, 2017

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronopathy, distal hereditary motor, type 7B

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases

Benign:1

Feb 09, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Perry syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.26

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

Eigen

Benign

0.082

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;.;D

M_CAP

Benign

0.076

MetaRNN

Benign

0.15

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

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.5

L;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.15

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

REVEL

Uncertain

0.45

Sift

Benign

0.34

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

Sift4G

Benign

0.55

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

Polyphen

0.84

P;.;.;B;.;.;.;.

Vest4

0.75

MutPred

0.30

Gain of helix (P = 0.2294);.;.;.;.;.;.;.;

MVP

0.83

MPC

0.34

ClinPred

0.080

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.094

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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