NM_004082.5:c.214A>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM1PM2PP3_Strong

The NM_004082.5(DCTN1):​c.214A>C​(p.Thr72Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: not found (cov: 32)

Consequence

DCTN1
NM_004082.5 missense

Scores

11
7
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 6.19
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS1
Transcript NM_004082.5 (DCTN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_004082.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DCTN1NM_004082.5 linkc.214A>C p.Thr72Pro missense_variant Exon 2 of 32 ENST00000628224.3 NP_004073.2 Q14203-1Q6MZZ3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DCTN1ENST00000628224.3 linkc.214A>C p.Thr72Pro missense_variant Exon 2 of 32 5 NM_004082.5 ENSP00000487279.2 Q14203-1E7EX90

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Neuronopathy, distal hereditary motor, type 7B;C1862939:Amyotrophic lateral sclerosis type 1;C1868594:Perry syndrome Uncertain:1
Jan 10, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 72 of the DCTN1 protein (p.Thr72Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Perry syndrome (PMID: 19136952, 24797316). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2664466). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DCTN1 protein function. Experimental studies have shown that this missense change affects DCTN1 function (PMID: 20518521). 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
Jan 06, 2016
Inherited Neuropathy Consortium Ii, University Of Miami
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.77
D;.;D;.;D;.;.;D;D;.;D;D;.
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
D;D;D;D;.;D;D;D;D;D;.;D;D
M_CAP
Pathogenic
0.51
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.5
M;M;.;.;.;M;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-4.2
D;D;.;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0030
D;D;.;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.010
D;D;D;D;D;D;.;.;D;.;D;D;D
Polyphen
0.99
D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.70
MutPred
0.90
Gain of ubiquitination at K77 (P = 0.0918);Gain of ubiquitination at K77 (P = 0.0918);.;.;.;Gain of ubiquitination at K77 (P = 0.0918);.;.;.;.;.;.;.;
MVP
0.99
MPC
1.6
ClinPred
0.99
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
gMVP
0.90

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs72466486; hg19: chr2-74605192; API