rs909177

Variant names:

• chr2-74367887-G-A
• rs909177
• NM_004082.5:c.2016-23C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004082.5(DCTN1):​c.2016-23C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,614,120 control chromosomes in the GnomAD database, including 16,747 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1588 hom., cov: 32)
  • Exomes 𝑓: 0.12 (15159 hom.)
• Consequence: DCTN1 NM_004082.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.721
• Publications: 17 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 (BayesDel_noAF=-0.81).
• BP6: Variant 2-74367887-G-A is Benign according to our data. Variant chr2-74367887-G-A is described in ClinVar as Benign. ClinVar VariationId is 259234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCTN1	NM_004082.5	c.2016-23C>T		intron_variant	Intron 17 of 31	ENST00000628224.3	NP_004073.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCTN1	ENST00000628224.3	c.2016-23C>T		intron_variant	Intron 17 of 31	5	NM_004082.5	ENSP00000487279.2

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19195 AN: 152124 Hom.: 1584 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.135

GnomAD2 exomes AF: 0.141 AC: 35464 AN: 250790 AF XY: 0.144

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.0756

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.469

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.124 AC: 181682 AN: 1461878 Hom.: 15159 Cov.: 32 AF XY: 0.127 AC XY: 92266 AN XY: 727242

African (AFR) AF: 0.108 AC: 3620 AN: 33480

American (AMR) AF: 0.0817 AC: 3653 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2992 AN: 26136

East Asian (EAS) AF: 0.520 AC: 20647 AN: 39700

South Asian (SAS) AF: 0.187 AC: 16120 AN: 86258

European-Finnish (FIN) AF: 0.111 AC: 5912 AN: 53416

Middle Eastern (MID) AF: 0.137 AC: 788 AN: 5768

European-Non Finnish (NFE) AF: 0.108 AC: 119646 AN: 1112000

Other (OTH) AF: 0.137 AC: 8304 AN: 60396

GnomAD4 genome AF: 0.126 AC: 19202 AN: 152242 Hom.: 1588 Cov.: 32 AF XY: 0.129 AC XY: 9622 AN XY: 74434

African (AFR) AF: 0.119 AC: 4931 AN: 41538

American (AMR) AF: 0.107 AC: 1644 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 391 AN: 3470

East Asian (EAS) AF: 0.457 AC: 2358 AN: 5162

South Asian (SAS) AF: 0.203 AC: 981 AN: 4822

European-Finnish (FIN) AF: 0.105 AC: 1115 AN: 10622

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7259 AN: 68012

Other (OTH) AF: 0.134 AC: 282 AN: 2110

Alfa AF: 0.114 Hom.: 822

Bravo AF: 0.129

Asia WGS AF: 0.320 AC: 1109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.61
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

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: rs909177; hg19: chr2-74595014; COSMIC: COSV62619575; COSMIC: COSV62619575;