2-74377768-T-C

Variant names:

• chr2-74377768-T-C
• rs3815241
• NM_004082.5:c.280-42A>G

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.280-42A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,579,042 control chromosomes in the GnomAD database, including 13,234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1357 hom., cov: 32)
  • Exomes 𝑓: 0.10 (11877 hom.)
• Consequence: DCTN1 NM_004082.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.85
• Publications: 7 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=-0.72).
• BP6: Variant 2-74377768-T-C is Benign according to our data. Variant chr2-74377768-T-C is described in ClinVar as Benign. ClinVar VariationId is 259237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCTN1	NM_004082.5	c.280-42A>G		intron_variant	Intron 2 of 31	ENST00000628224.3	NP_004073.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCTN1	ENST00000628224.3	c.280-42A>G		intron_variant	Intron 2 of 31	5	NM_004082.5	ENSP00000487279.2

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16888 AN: 152074 Hom.: 1355 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.0879

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0948

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0786

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.126 AC: 31535 AN: 250234 AF XY: 0.129

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0605

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.471

Gnomad FIN exome AF: 0.0951

Gnomad NFE exome AF: 0.0804

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.102 AC: 145412 AN: 1426850 Hom.: 11877 Cov.: 25 AF XY: 0.105 AC XY: 74658 AN XY: 712266

African (AFR) AF: 0.111 AC: 3621 AN: 32712

American (AMR) AF: 0.0656 AC: 2931 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 3313 AN: 25936

East Asian (EAS) AF: 0.521 AC: 20573 AN: 39492

South Asian (SAS) AF: 0.189 AC: 16202 AN: 85518

European-Finnish (FIN) AF: 0.0968 AC: 5170 AN: 53384

Middle Eastern (MID) AF: 0.117 AC: 666 AN: 5698

European-Non Finnish (NFE) AF: 0.0795 AC: 85888 AN: 1080186

Other (OTH) AF: 0.119 AC: 7048 AN: 59246

GnomAD4 genome AF: 0.111 AC: 16895 AN: 152192 Hom.: 1357 Cov.: 32 AF XY: 0.115 AC XY: 8578 AN XY: 74412

African (AFR) AF: 0.120 AC: 4968 AN: 41514

American (AMR) AF: 0.0877 AC: 1342 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 434 AN: 3472

East Asian (EAS) AF: 0.458 AC: 2356 AN: 5148

South Asian (SAS) AF: 0.210 AC: 1012 AN: 4824

European-Finnish (FIN) AF: 0.0948 AC: 1006 AN: 10608

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0786 AC: 5347 AN: 68012

Other (OTH) AF: 0.112 AC: 236 AN: 2110

Alfa AF: 0.0943 Hom.: 193

Bravo AF: 0.112

Asia WGS AF: 0.326 AC: 1128 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

- -

Oct 01, 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	-0.72
CADD	Benign	3.9
DANN	Benign	0.83
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3815241; hg19: chr2-74604895; COSMIC: COSV62620546; COSMIC: COSV62620546;