NM_004082.5:c.1484G>A

Variant names:

• chr2-74369400-C-T
• rs17721059
• NM_004082.5:c.1484G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004082.5(DCTN1):​c.1484G>A​(p.Arg495Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,614,178 control chromosomes in the GnomAD database, including 279 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R495W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 32)
  • Exomes 𝑓: 0.017 (254 hom.)
• Consequence: DCTN1 NM_004082.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 3.26
• Publications: 21 publications found

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• distal hereditary motor neuropathy type 7

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0082784).
• BP6: Variant 2-74369400-C-T is Benign according to our data. Variant chr2-74369400-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259232.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0131 (1989/152294) while in subpopulation NFE AF = 0.0192 (1308/68020). AF 95% confidence interval is 0.0184. There are 25 homozygotes in GnomAd4. There are 905 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1989 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCTN1	NM_004082.5	MANE Select	c.1484G>A	p.Arg495Gln	missense	Exon 14 of 32	NP_004073.2
	DCTN1	NM_001190837.2		c.1463G>A	p.Arg488Gln	missense	Exon 13 of 31	NP_001177766.1	Q14203-6
	DCTN1	NM_001378991.1		c.1433G>A	p.Arg478Gln	missense	Exon 14 of 32	NP_001365920.1	A0A7P0Z4C3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCTN1	ENST00000628224.3	TSL:5 MANE Select	c.1484G>A	p.Arg495Gln	missense	Exon 14 of 32	ENSP00000487279.2	Q14203-1
	DCTN1	ENST00000361874.8	TSL:1	c.1484G>A	p.Arg495Gln	missense	Exon 14 of 31	ENSP00000354791.4	A0A804CDA6
	DCTN1	ENST00000409567.7	TSL:1	c.1424G>A	p.Arg475Gln	missense	Exon 11 of 28	ENSP00000386843.3	Q14203-4

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1989 AN: 152176 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0137 AC: 3446 AN: 251160 AF XY: 0.0143

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0263

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00591

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0168 AC: 24507 AN: 1461884 Hom.: 254 Cov.: 32 AF XY: 0.0165 AC XY: 11970 AN XY: 727246

African (AFR) AF: 0.00320 AC: 107 AN: 33480

American (AMR) AF: 0.0143 AC: 638 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0243 AC: 635 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.00541 AC: 467 AN: 86258

European-Finnish (FIN) AF: 0.00663 AC: 354 AN: 53414

Middle Eastern (MID) AF: 0.0133 AC: 77 AN: 5768

European-Non Finnish (NFE) AF: 0.0191 AC: 21210 AN: 1112008

Other (OTH) AF: 0.0168 AC: 1014 AN: 60396

GnomAD4 genome AF: 0.0131 AC: 1989 AN: 152294 Hom.: 25 Cov.: 32 AF XY: 0.0122 AC XY: 905 AN XY: 74470

African (AFR) AF: 0.00339 AC: 141 AN: 41560

American (AMR) AF: 0.0192 AC: 293 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4822

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0192 AC: 1308 AN: 68020

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0188 Hom.: 105

Bravo AF: 0.0142

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0186 AC: 160

ExAC AF: 0.0132 AC: 1597

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0230

EpiControl AF: 0.0258

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	1	-	Amyotrophic lateral sclerosis (1)
-	-	1	Neuronopathy, distal hereditary motor, type 7B (1)
-	-	1	Neuronopathy, distal hereditary motor, type 7B;C1862939:Amyotrophic lateral sclerosis type 1;C1868594:Perry syndrome (1)
-	-	1	Perry syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.022
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.14
Sift	Benign	0.22	T
Sift4G	Benign	0.32	T
Polyphen		0.80	P
Vest4		0.087
MPC		0.76
ClinPred		0.018	T
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.075
gMVP		0.32
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs17721059; hg19: chr2-74596527;