rs1130484

Positions:

• chr2-74366801-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004082.5(DCTN1):​c.2448A>G​(p.Ala816Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00893 in 1,614,236 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (57 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (98 hom.)
• Consequence: DCTN1 NM_004082.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.97

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-74366801-T-C is Benign according to our data. Variant chr2-74366801-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 259235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74366801-T-C is described in Lovd as [Benign]. Variant chr2-74366801-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.97 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0177 (2696/152342) while in subpopulation AFR AF= 0.0436 (1814/41572). AF 95% confidence interval is 0.042. There are 57 homozygotes in gnomad4. There are 1290 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2696 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCTN1	NM_004082.5	c.2448A>G	p.Ala816Ala	synonymous_variant	21/32	ENST00000628224.3	NP_004073.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCTN1	ENST00000628224.3	c.2448A>G	p.Ala816Ala	synonymous_variant	21/32	5	NM_004082.5	ENSP00000487279.2

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2687 AN: 152224 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.0435

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00692

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0101 AC: 2539 AN: 251492 Hom.: 36 AF XY: 0.0100 AC XY: 1365 AN XY: 135922

Gnomad AFR exome AF: 0.0450

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.0306

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0140

Gnomad FIN exome AF: 0.00323

Gnomad NFE exome AF: 0.00695

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00801 AC: 11714 AN: 1461894 Hom.: 98 Cov.: 33 AF XY: 0.00803 AC XY: 5839 AN XY: 727248

Gnomad4 AFR exome AF: 0.0480

Gnomad4 AMR exome AF: 0.00467

Gnomad4 ASJ exome AF: 0.0279

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0145

Gnomad4 FIN exome AF: 0.00344

Gnomad4 NFE exome AF: 0.00634

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.0177 AC: 2696 AN: 152342 Hom.: 57 Cov.: 32 AF XY: 0.0173 AC XY: 1290 AN XY: 74490

Gnomad4 AFR AF: 0.0436

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.0253

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00692

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0135 Hom.: 9

Bravo AF: 0.0195

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00774

EpiControl AF: 0.00551

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 10, 2021	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -

Neuronopathy, distal hereditary motor, type 7B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Perry syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.4
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1130484; hg19: chr2-74593928; COSMIC: COSV62621026; COSMIC: COSV62621026;