rs909177

chr2-74367887-G-A

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: 0.721

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 Benign. Variant got -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 id 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/exons	MANE	UniProt
DCTN1	NM_004082.5	c.2016-23C>T		intron_variant		ENST00000628224.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCTN1	ENST00000628224.3	c.2016-23C>T		intron_variant		5	NM_004082.5	A1

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

GnomAD3 exomes AF: 0.141 AC: 35464 AN: 250790 Hom.: 3799 AF XY: 0.144 AC XY: 19505 AN XY: 135584

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 SAS exome AF: 0.186

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

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.0817

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.520

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.137

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

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.457

Gnomad4 SAS AF: 0.203

Gnomad4 FIN AF: 0.105

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.134

Alfa AF: 0.115 Hom.: 632

Bravo AF: 0.129

Asia WGS AF: 0.320 AC: 1109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	12
Dann	Benign	0.61

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

Publications

LitVar

Other links and lift over

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