2-74371625-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004082.5(DCTN1):​c.557C>G​(p.Pro186Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000834 in 1,438,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

DCTN1
NM_004082.5 missense

Scores

4
14
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.08
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DCTN1NM_004082.5 linkc.557C>G p.Pro186Arg missense_variant Exon 8 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.557C>G p.Pro186Arg missense_variant Exon 8 of 32 5 NM_004082.5 ENSP00000487279.2 Q14203-1E7EX90

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000834
AC:
12
AN:
1438700
Hom.:
0
Cov.:
32
AF XY:
0.00000841
AC XY:
6
AN XY:
713362
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:
0.0000109
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
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
Dec 12, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 186 of the DCTN1 protein (p.Pro186Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DCTN1-related conditions. 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%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
D;.;T;.;.;.;T;.
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D;.;D
M_CAP
Uncertain
0.16
D
MetaRNN
Uncertain
0.52
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.0024
T
MutationAssessor
Uncertain
2.4
M;.;.;.;.;.;.;.
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-4.0
D;D;.;.;D;D;D;D
REVEL
Uncertain
0.45
Sift
Uncertain
0.0090
D;D;.;.;T;D;D;D
Sift4G
Uncertain
0.0050
D;D;D;D;D;D;D;D
Polyphen
1.0
D;.;.;D;.;.;.;.
Vest4
0.61
MutPred
0.23
Loss of glycosylation at P186 (P = 0.0127);.;.;.;.;.;.;.;
MVP
0.98
MPC
1.5
ClinPred
0.97
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.21
gMVP
0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-74598752; API