rs1130484

Variant names:

• chr2-74366801-T-C
• rs1130484
• NM_004082.5:c.2448A>G

Variant summary

Our verdict is Benign. The variant received -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:12
• Conservation: PhyloP100: -2.97
• Publications: 8 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 -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 Benign/Likely_benign. ClinVar VariationId is 259235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2696 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004082.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCTN1	NM_004082.5	MANE Select	c.2448A>G	p.Ala816Ala	synonymous	Exon 21 of 32	NP_004073.2
	DCTN1	NM_001190837.2		c.2427A>G	p.Ala809Ala	synonymous	Exon 20 of 31	NP_001177766.1	Q14203-6
	DCTN1	NM_001378991.1		c.2397A>G	p.Ala799Ala	synonymous	Exon 21 of 32	NP_001365920.1	A0A7P0Z4C3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCTN1	ENST00000628224.3	TSL:5 MANE Select	c.2448A>G	p.Ala816Ala	synonymous	Exon 21 of 32	ENSP00000487279.2	Q14203-1
	DCTN1	ENST00000361874.8	TSL:1	c.2448A>G	p.Ala816Ala	synonymous	Exon 21 of 31	ENSP00000354791.4	A0A804CDA6
	DCTN1	ENST00000409567.7	TSL:1	c.2388A>G	p.Ala796Ala	synonymous	Exon 18 of 28	ENSP00000386843.3	Q14203-4

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

GnomAD2 exomes AF: 0.0101 AC: 2539 AN: 251492 AF XY: 0.0100

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 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

African (AFR) AF: 0.0480 AC: 1606 AN: 33480

American (AMR) AF: 0.00467 AC: 209 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 730 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0145 AC: 1250 AN: 86258

European-Finnish (FIN) AF: 0.00344 AC: 184 AN: 53420

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5768

European-Non Finnish (NFE) AF: 0.00634 AC: 7055 AN: 1112012

Other (OTH) AF: 0.0101 AC: 609 AN: 60396

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

African (AFR) AF: 0.0436 AC: 1814 AN: 41572

American (AMR) AF: 0.0137 AC: 210 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 88 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4824

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00692 AC: 471 AN: 68034

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0130 Hom.: 17

Bravo AF: 0.0195

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00774

EpiControl AF: 0.00551

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Neuronopathy, distal hereditary motor, type 7B (1)
-	-	1	Neuronopathy, distal hereditary motor, type 7B;C1862939:Amyotrophic lateral sclerosis type 1;C1868594:Perry syndrome (1)
-	-	1	Perry syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.4
DANN	Benign	0.47
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1130484; hg19: chr2-74593928; COSMIC: COSV62621026; COSMIC: COSV62621026;