rs72466494

Variant names:

• chr2-74362989-C-T
• rs72466494
• NM_004082.5:c.3529+5G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_004082.5(DCTN1):​c.3529+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00815 in 1,611,326 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (48 hom.)
• Consequence: DCTN1 NM_004082.5 splice_region, intron
• Scores: Splicing: ADA: 0.9988
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.89
• Publications: 3 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

ENSG00000264324 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 2-74362989-C-T is Benign according to our data. Variant chr2-74362989-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284990.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 = 0.00628 (956/152270) while in subpopulation AMR AF = 0.00908 (139/15300). AF 95% confidence interval is 0.00818. There are 2 homozygotes in GnomAd4. There are 469 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 956 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.3529+5G>A		splice_region intron	N/A	NP_004073.2
	DCTN1	NM_001190837.2		c.3508+5G>A		splice_region intron	N/A	NP_001177766.1	Q14203-6
	DCTN1	NM_001378991.1		c.3478+5G>A		splice_region intron	N/A	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.3529+5G>A		splice_region intron	N/A	ENSP00000487279.2	Q14203-1
	DCTN1	ENST00000361874.8	TSL:1	c.3514+5G>A		splice_region intron	N/A	ENSP00000354791.4	A0A804CDA6
	DCTN1	ENST00000409567.7	TSL:1	c.3454+5G>A		splice_region intron	N/A	ENSP00000386843.3	Q14203-4

Frequencies

GnomAD3 genomes AF: 0.00628 AC: 956 AN: 152152 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00910

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00717

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00876

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00600 AC: 1484 AN: 247518 AF XY: 0.00606

Gnomad AFR exome AF: 0.00212

Gnomad AMR exome AF: 0.00495

Gnomad ASJ exome AF: 0.00561

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00777

Gnomad NFE exome AF: 0.00876

Gnomad OTH exome AF: 0.00713

GnomAD4 exome AF: 0.00834 AC: 12175 AN: 1459056 Hom.: 48 Cov.: 32 AF XY: 0.00809 AC XY: 5873 AN XY: 725608

African (AFR) AF: 0.00191 AC: 64 AN: 33438

American (AMR) AF: 0.00467 AC: 208 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00575 AC: 149 AN: 25900

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00118 AC: 101 AN: 85782

European-Finnish (FIN) AF: 0.00680 AC: 362 AN: 53198

Middle Eastern (MID) AF: 0.00692 AC: 38 AN: 5488

European-Non Finnish (NFE) AF: 0.00971 AC: 10790 AN: 1110760

Other (OTH) AF: 0.00768 AC: 463 AN: 60272

GnomAD4 genome AF: 0.00628 AC: 956 AN: 152270 Hom.: 2 Cov.: 32 AF XY: 0.00630 AC XY: 469 AN XY: 74448

African (AFR) AF: 0.00205 AC: 85 AN: 41560

American (AMR) AF: 0.00908 AC: 139 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00717 AC: 76 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00876 AC: 596 AN: 68016

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00693 Hom.: 4

Bravo AF: 0.00618

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	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
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Benign	0.94
PhyloP100		4.9
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.080		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: rs72466494; hg19: chr2-74590116;