2-74362161-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004082.5(DCTN1):c.3610-20C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0481 in 1,610,734 control chromosomes in the GnomAD database, including 5,566 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.093 ( 1369 hom., cov: 32)

Exomes 𝑓: 0.043 ( 4197 hom. )

Consequence

DCTN1
NM_004082.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.563

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis type 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
neuronopathy, distal hereditary motor, type 7B
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Perry syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
amyotrophic lateral sclerosis
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
distal hereditary motor neuropathy type 7
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DCTN1 links:

ENSG00000264324 (HGNC:):

ENSG00000264324 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 2-74362161-G-C is Benign according to our data. Variant chr2-74362161-G-C is described in ClinVar as [Benign]. Clinvar id is 259239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCTN1	NM_004082.5 link	c.3610-20C>G		intron_variant	Intron 30 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.3610-20C>G		intron_variant	Intron 30 of 31	5	NM_004082.5	ENSP00000487279.2		Q14203-1E7EX90
ENSG00000264324	ENST00000451608.2 link	n.349-20C>G		intron_variant	Intron 3 of 38	5		ENSP00000416453.2		E7EWF7

Frequencies

GnomAD3 genomes

AF:

0.0929

AC:

14125

AN:

152020

Hom.:

1363

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.114

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.367

Gnomad SAS

AF:

0.0520

Gnomad FIN

AF:

0.0174

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0243

Gnomad OTH

AF:

0.0770

GnomAD2 exomes

AF:

0.0829

AC:

20793

AN:

250796

AF XY:

0.0727

show subpopulations

Gnomad AFR exome

AF:

0.211

Gnomad AMR exome

AF:

0.160

Gnomad ASJ exome

AF:

0.00844

Gnomad EAS exome

AF:

0.375

Gnomad FIN exome

AF:

0.0168

Gnomad NFE exome

AF:

0.0263

Gnomad OTH exome

AF:

0.0555

GnomAD4 exome

AF:

0.0434

AC:

63319

AN:

1458596

Hom.:

4197

Cov.:

AF XY:

0.0416

AC XY:

30174

AN XY:

725728

show subpopulations

African (AFR)

AF:

0.210

AC:

7023

AN:

33396

American (AMR)

AF:

0.158

AC:

7070

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00740

AC:

193

AN:

26096

East Asian (EAS)

AF:

0.314

AC:

12434

AN:

39646

South Asian (SAS)

AF:

0.0389

AC:

3351

AN:

86134

European-Finnish (FIN)

AF:

0.0185

AC:

984

AN:

53210

Middle Eastern (MID)

AF:

0.0271

AC:

156

AN:

5762

European-Non Finnish (NFE)

AF:

0.0257

AC:

28490

AN:

1109446

Other (OTH)

AF:

0.0600

AC:

3618

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

3157

6314

9470

12627

15784

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1406

2812

4218

5624

7030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0930

AC:

14149

AN:

152138

Hom.:

1369

Cov.:

AF XY:

0.0927

AC XY:

6893

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.198

AC:

8222

AN:

41470

American (AMR)

AF:

0.114

AC:

1748

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.367

AC:

1890

AN:

5152

South Asian (SAS)

AF:

0.0516

AC:

249

AN:

4826

European-Finnish (FIN)

AF:

0.0174

AC:

185

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0243

AC:

1655

AN:

67990

Other (OTH)

AF:

0.0791

AC:

167

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

588

1176

1765

2353

2941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

296

444

592

740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0221

Hom.:

Bravo

AF:

0.110

Asia WGS

AF:

0.193

AC:

670

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Feb 03, 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

-0.76

CADD

Benign

8.6

(source)

DANN

Benign

0.83

PhyloP100

0.56

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over