rs372546194

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004082.5(DCTN1):c.1482G>A(p.Ala494Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,614,092 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

DCTN1
NM_004082.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.901

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 2-74369402-C-T is Benign according to our data. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74369402-C-T is described in CliVar as Likely_benign. Clinvar id is 468256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.901 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000854 (13/152208) while in subpopulation SAS AF = 0.00186 (9/4828). AF 95% confidence interval is 0.000972. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCTN1	NM_004082.5 link	c.1482G>A	p.Ala494Ala	synonymous_variant	Exon 14 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.1482G>A	p.Ala494Ala	synonymous_variant	Exon 14 of 32	5	NM_004082.5	ENSP00000487279.2		Q14203-1E7EX90

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000916

AC:

AN:

251132

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000522

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000279

AC:

AN:

1112008

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000854

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00186

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000579

Hom.:

Bravo

AF:

0.0000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Jul 11, 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. -

DCTN1-related disorder

Benign:1

Nov 22, 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

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

-0.46

CADD

Benign

5.4

(source)

DANN

Benign

0.63

PhyloP100

-0.90

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Mutation Taster

=100/0

polymorphism

(source)

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

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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