rs72659383

Variant names:

• chr2-74365125-C-T
• rs72659383
• NM_004082.5:c.3146G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004082.5(DCTN1):​c.3146G>A​(p.Arg1049Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,142 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1049W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (1 hom.)
• Consequence: DCTN1 NM_004082.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:14
• Conservation: PhyloP100: 7.53
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020893872).
• BP6: Variant 2-74365125-C-T is Benign according to our data. Variant chr2-74365125-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 337078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00156 (237/152252) while in subpopulation AMR AF = 0.00491 (75/15286). AF 95% confidence interval is 0.00401. There are 0 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 237 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.3146G>A	p.Arg1049Gln	missense	Exon 26 of 32	NP_004073.2
	DCTN1	NM_001190837.2		c.3125G>A	p.Arg1042Gln	missense	Exon 25 of 31	NP_001177766.1	Q14203-6
	DCTN1	NM_001378991.1		c.3095G>A	p.Arg1032Gln	missense	Exon 26 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.3146G>A	p.Arg1049Gln	missense	Exon 26 of 32	ENSP00000487279.2	Q14203-1
	DCTN1	ENST00000361874.8	TSL:1	c.3146G>A	p.Arg1049Gln	missense	Exon 26 of 31	ENSP00000354791.4	A0A804CDA6
	DCTN1	ENST00000409567.7	TSL:1	c.3086G>A	p.Arg1029Gln	missense	Exon 23 of 28	ENSP00000386843.3	Q14203-4

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00108 AC: 271 AN: 251476 AF XY: 0.00117

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00180

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00146 AC: 2139 AN: 1461890 Hom.: 1 Cov.: 31 AF XY: 0.00144 AC XY: 1046 AN XY: 727246

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.00139 AC: 62 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00177 AC: 1968 AN: 1112010

Other (OTH) AF: 0.00137 AC: 83 AN: 60396

GnomAD4 genome AF: 0.00156 AC: 237 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.00175 AC XY: 130 AN XY: 74448

African (AFR) AF: 0.000457 AC: 19 AN: 41532

American (AMR) AF: 0.00491 AC: 75 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00200 AC: 136 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00158 Hom.: 1

Bravo AF: 0.00133

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.000988 AC: 120

EpiCase AF: 0.00174

EpiControl AF: 0.00184

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	3	not specified (3)
-	1	1	Perry syndrome (2)
-	-	1	DCTN1-related disorder (1)
-	-	1	Inborn genetic diseases (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.086	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.27
Sift	Benign	0.22	T
Sift4G	Benign	0.26	T
Polyphen		0.99	D
Vest4		0.53
MVP		0.92
MPC		0.52
ClinPred		0.036	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.075
gMVP		0.27
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs72659383; hg19: chr2-74592252; COSMIC: COSV107450351; COSMIC: COSV107450351;