2-74362161-G-C

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.3610-20C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0481 in 1,610,734 control chromosomes in the GnomAD database, including 5,566 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (1369 hom., cov: 32)
  • Exomes 𝑓: 0.043 (4197 hom.)
• Consequence: DCTN1 NM_004082.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.563

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=-0.76).
• BP6: Variant 2-74362161-G-C is Benign according to our data. Variant chr2-74362161-G-C is described in ClinVar as [Benign]. Clinvar id is 259239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74362161-G-C is described in Lovd as [Benign]. Variant chr2-74362161-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCTN1	NM_004082.5	c.3610-20C>G		intron_variant		ENST00000628224.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCTN1	ENST00000628224.3	c.3610-20C>G		intron_variant		5	NM_004082.5	A1

Frequencies

GnomAD3 genomes AF: 0.0929 AC: 14125 AN: 152020 Hom.: 1363 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.0520

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0243

Gnomad OTH AF: 0.0770

GnomAD3 exomes AF: 0.0829 AC: 20793 AN: 250796 Hom.: 2234 AF XY: 0.0727 AC XY: 9853 AN XY: 135540

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.375

Gnomad SAS exome AF: 0.0395

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.0263

Gnomad OTH exome AF: 0.0555

GnomAD4 exome AF: 0.0434 AC: 63319 AN: 1458596 Hom.: 4197 Cov.: 30 AF XY: 0.0416 AC XY: 30174 AN XY: 725728

Gnomad4 AFR exome AF: 0.210

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.00740

Gnomad4 EAS exome AF: 0.314

Gnomad4 SAS exome AF: 0.0389

Gnomad4 FIN exome AF: 0.0185

Gnomad4 NFE exome AF: 0.0257

Gnomad4 OTH exome AF: 0.0600

GnomAD4 genome AF: 0.0930 AC: 14149 AN: 152138 Hom.: 1369 Cov.: 32 AF XY: 0.0927 AC XY: 6893 AN XY: 74364

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.367

Gnomad4 SAS AF: 0.0516

Gnomad4 FIN AF: 0.0174

Gnomad4 NFE AF: 0.0243

Gnomad4 OTH AF: 0.0791

Alfa AF: 0.0221 Hom.: 33

Bravo AF: 0.110

Asia WGS AF: 0.193 AC: 670 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Neuronopathy, distal hereditary motor, type 7B;C1862939:Amyotrophic lateral sclerosis type 1;C1868594:Perry syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	8.6
Dann	Benign	0.83

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: rs2268427; hg19: chr2-74589288; COSMIC: COSV62621764; COSMIC: COSV62621764;