rs121909345

Positions:

chr2-74363337-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_004082.5(DCTN1):c.3302G>A(p.Arg1101Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,272 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

DCTN1
NM_004082.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 2.73

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29399675).

BS2

High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCTN1	NM_004082.5 linkuse as main transcript	c.3302G>A	p.Arg1101Lys	missense_variant	28/32	ENST00000628224.3	NP_004073.2	Q14203-1Q6MZZ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCTN1	ENST00000628224.3 linkuse as main transcript	c.3302G>A	p.Arg1101Lys	missense_variant	28/32	5	NM_004082.5	ENSP00000487279.2		Q14203-1E7EX90
ENSG00000264324	ENST00000451608.2 linkuse as main transcript	n.41G>A		non_coding_transcript_exon_variant	1/39	5		ENSP00000416453.2		E7EWF7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152182

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

249326

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134758

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000621

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461090

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726730

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000341

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 18, 2024

Variant summary: DCTN1 c.3302G>A (p.Arg1101Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249326 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3302G>A has been reported in the literature as heterozygous genotype in individuals affected with DCTN1-Related amyotrophic lateral sclerosis and frontotemporal dementia (FTD) in two siblings in one family respectively (Munch_2005). These report(s) do not provide unequivocal conclusions about association of the variant with DCTN1-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Stockmann_2013). The following publications have been ascertained in the context of this evaluation (PMID: 16240349, 23143281). ClinVar contains an entry for this variant (Variation ID: 8405). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2021

The p.R1101K variant (also known as c.3302G>A), located in coding exon 28 of the DCTN1 gene, results from a G to A substitution at nucleotide position 3302. The arginine at codon 1101 is replaced by lysine, an amino acid with highly similar properties. This variant was identified in the heterozygous state in a pair of siblings, one of whom had amyotrophic lateral sclerosis (ALS) and one of whom had frontotemporal dementia (FTD) (Münch C et al. Ann Neurol, 2005 Nov;58:777-80). In vitro experimental studies show that this alteration does not significantly impact protein function (Dixit R et al. J Biol Chem, 2008 Nov;283:33611-9; Stockmann M et al. J Neural Transm (Vienna), 2013 May;120:785-98). This amino acid position is well conserved in available vertebrate species; however, lysine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1101 of the DCTN1 protein (p.Arg1101Lys). This variant is present in population databases (rs121909345, gnomAD 0.006%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis and frontotemporal dementia (PMID: 16240349). ClinVar contains an entry for this variant (Variation ID: 8405). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DCTN1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect DCTN1 function (PMID: 18812314, 23143281). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Perry syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium Ii, University Of Miami

Jan 06, 2016

- -

Amyotrophic lateral sclerosis, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Nov 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

0.0020

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.081

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

Eigen

Benign

-0.084

Eigen_PC

Benign

0.094

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

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

M_CAP

Benign

0.024

MetaRNN

Benign

0.29

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

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.60

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

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.13

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

REVEL

Uncertain

0.30

Sift

Benign

0.33

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

Sift4G

Benign

0.39

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

Polyphen

0.0020

B;.;.;B;.;.;.;.

Vest4

0.57

MutPred

0.70

Gain of ubiquitination at R1101 (P = 0.0162);.;.;.;.;.;.;.;

MVP

0.69

MPC

0.12

ClinPred

0.11

GERP RS

4.8

Varity_R

0.081

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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