2-74378220-G-A

Position:

• chr2-74378220-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004082.5(DCTN1):​c.59C>T​(p.Ala20Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,458,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A20A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: DCTN1 NM_004082.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.80

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09575936).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCTN1	NM_004082.5	c.59C>T	p.Ala20Val	missense_variant	2/32	ENST00000628224.3	NP_004073.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCTN1	ENST00000628224.3	c.59C>T	p.Ala20Val	missense_variant	2/32	5	NM_004082.5	ENSP00000487279	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247772 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134304

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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1458150 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 725676

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronopathy, distal hereditary motor, type 7B Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Perry syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -

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

Oct 15, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 20 of the DCTN1 protein (p.Ala20Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DCTN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 337098). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	Benign	0.083
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.086	T;.;T;.;T;.;.;T;T;.;T;T;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T;T;T;T;.;T;T;T;T;T;.;T;T;.
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.096	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.69	N;N;.;.;.;N;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.40	N;N;.;N;N;N;N;N;N;N;N;N;N;D
REVEL	Benign	0.15
Sift	Benign	0.33	T;T;.;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.37	T;T;T;T;T;T;.;.;T;.;T;T;T;.
Polyphen		0.0	B;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.13
MutPred		0.16		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;.;Loss of helix (P = 0.1299);.;.;.;.;.;.;.;.;
MVP		0.79
MPC		0.58
ClinPred		0.078	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.019
gMVP		0.48

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

Other links and lift over

dbSNP: rs773420384; hg19: chr2-74605347; COSMIC: COSV62621689; COSMIC: COSV62621689;