Genetic Variant DCTN1:p.Pro209Pro (chr2-74371555-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_004082.5(DCTN1):c.627G>A(p.Pro209Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000919 in 1,578,248 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 (★). Synonymous variant affecting the same amino acid position (i.e. P209P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

DCTN1
NM_004082.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.947

Publications

1 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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 2-74371555-C-T is Benign according to our data. Variant chr2-74371555-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1084107.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.947 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000315 (48/152162) while in subpopulation AFR AF = 0.00101 (42/41522). AF 95% confidence interval is 0.000769. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 48 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004082.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DCTN1	NM_004082.5	MANE Select	c.627G>A	p.Pro209Pro	synonymous	Exon 8 of 32	NP_004073.2
DCTN1	NM_001190837.2		c.606G>A	p.Pro202Pro	synonymous	Exon 7 of 31	NP_001177766.1
DCTN1	NM_001378991.1		c.576G>A	p.Pro192Pro	synonymous	Exon 8 of 32	NP_001365920.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DCTN1	ENST00000628224.3	TSL:5 MANE Select	c.627G>A	p.Pro209Pro	synonymous	Exon 8 of 32	ENSP00000487279.2
DCTN1	ENST00000361874.8	TSL:1	c.627G>A	p.Pro209Pro	synonymous	Exon 8 of 31	ENSP00000354791.4
DCTN1	ENST00000409567.7	TSL:1	c.567G>A	p.Pro189Pro	synonymous	Exon 5 of 28	ENSP00000386843.3

Frequencies

GnomAD3 genomes

AF:

0.000316

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

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:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000828

AC:

AN:

193130

AF XY:

0.000107

show subpopulations

Gnomad AFR exome

AF:

0.000427

Gnomad AMR exome

AF:

0.0000704

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000675

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000680

AC:

AN:

1426086

Hom.:

Cov.:

AF XY:

0.0000680

AC XY:

AN XY:

705912

show subpopulations

African (AFR)

AF:

0.000945

AC:

AN:

32808

American (AMR)

AF:

0.000102

AC:

AN:

39320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25436

East Asian (EAS)

AF:

0.0000786

AC:

AN:

38156

South Asian (SAS)

AF:

0.000197

AC:

AN:

81298

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51178

Middle Eastern (MID)

AF:

0.000215

AC:

AN:

4656

European-Non Finnish (NFE)

AF:

0.0000347

AC:

AN:

1094272

Other (OTH)

AF:

0.0000678

AC:

AN:

58962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.000315

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41522

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.00

Hom.:

Bravo

AF:

0.000325

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

DCTN1-related disorder

Benign:1

Jun 20, 2022

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

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.60

(source)

DANN

Benign

0.69

PhyloP100

-0.95

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over