rs72466494

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_004082.5(DCTN1):c.3529+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00815 in 1,611,326 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0083 ( 48 hom. )

Consequence

DCTN1
NM_004082.5 splice_region, intron

Scores

Splicing: ADA: 0.9988

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.89

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:

ENSG00000264324 (HGNC:):

ENSG00000264324 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 2-74362989-C-T is Benign according to our data. Variant chr2-74362989-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 284990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74362989-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00628 (956/152270) while in subpopulation AMR AF= 0.00908 (139/15300). AF 95% confidence interval is 0.00818. There are 2 homozygotes in gnomad4. There are 469 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 956 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCTN1	NM_004082.5 link	c.3529+5G>A		splice_region_variant, intron_variant	Intron 29 of 31	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.3529+5G>A		splice_region_variant, intron_variant	Intron 29 of 31	5	NM_004082.5	ENSP00000487279.2		Q14203-1E7EX90
ENSG00000264324	ENST00000451608.2 link	n.268+5G>A		splice_region_variant, intron_variant	Intron 2 of 38	5		ENSP00000416453.2		E7EWF7

Frequencies

GnomAD3 genomes

AF:

0.00628

AC:

956

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00910

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00717

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00876

Gnomad OTH

AF:

0.00861

GnomAD3 exomes

AF:

0.00600

AC:

1484

AN:

247518

Hom.:

AF XY:

0.00606

AC XY:

812

AN XY:

133938

show subpopulations

Gnomad AFR exome

AF:

0.00212

Gnomad AMR exome

AF:

0.00495

Gnomad ASJ exome

AF:

0.00561

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00126

Gnomad FIN exome

AF:

0.00777

Gnomad NFE exome

AF:

0.00876

Gnomad OTH exome

AF:

0.00713

GnomAD4 exome

AF:

0.00834

AC:

12175

AN:

1459056

Hom.:

Cov.:

AF XY:

0.00809

AC XY:

5873

AN XY:

725608

show subpopulations

Gnomad4 AFR exome

AF:

0.00191

Gnomad4 AMR exome

AF:

0.00467

Gnomad4 ASJ exome

AF:

0.00575

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00118

Gnomad4 FIN exome

AF:

0.00680

Gnomad4 NFE exome

AF:

0.00971

Gnomad4 OTH exome

AF:

0.00768

GnomAD4 genome

AF:

0.00628

AC:

956

AN:

152270

Hom.:

Cov.:

AF XY:

0.00630

AC XY:

469

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00205

Gnomad4 AMR

AF:

0.00908

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00717

Gnomad4 NFE

AF:

0.00876

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00711

Hom.:

Bravo

AF:

0.00618

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Dec 08, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 30, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DCTN1: BP4, BS2 -

Mar 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Perry syndrome

Benign:2

Jan 13, 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. -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Aug 28, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DCTN1-related disorder

Benign:1

Jun 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Benign

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.080

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