rs201078804

Variant names:

• chr2-74371624-C-T
• rs201078804
• NM_004082.5:c.558G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004082.5(DCTN1):​c.558G>A​(p.Pro186Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 1,590,864 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: DCTN1 NM_004082.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.05
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-74371624-C-T is Benign according to our data. Variant chr2-74371624-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000296 (45/152172) while in subpopulation AMR AF = 0.000588 (9/15300). AF 95% confidence interval is 0.000307. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 45 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.558G>A	p.Pro186Pro	synonymous	Exon 8 of 32	NP_004073.2
	DCTN1	NM_001190837.2		c.537G>A	p.Pro179Pro	synonymous	Exon 7 of 31	NP_001177766.1	Q14203-6
	DCTN1	NM_001378991.1		c.507G>A	p.Pro169Pro	synonymous	Exon 8 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.558G>A	p.Pro186Pro	synonymous	Exon 8 of 32	ENSP00000487279.2	Q14203-1
	DCTN1	ENST00000361874.8	TSL:1	c.558G>A	p.Pro186Pro	synonymous	Exon 8 of 31	ENSP00000354791.4	A0A804CDA6
	DCTN1	ENST00000409567.7	TSL:1	c.498G>A	p.Pro166Pro	synonymous	Exon 5 of 28	ENSP00000386843.3	Q14203-4

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000316 AC: 66 AN: 208648 AF XY: 0.000277

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000647

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.000191

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000435

Gnomad OTH exome AF: 0.000564

GnomAD4 exome AF: 0.000506 AC: 728 AN: 1438692 Hom.: 1 Cov.: 32 AF XY: 0.000478 AC XY: 341 AN XY: 713288

African (AFR) AF: 0.0000601 AC: 2 AN: 33256

American (AMR) AF: 0.000470 AC: 19 AN: 40432

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25560

East Asian (EAS) AF: 0.0000771 AC: 3 AN: 38914

South Asian (SAS) AF: 0.0000242 AC: 2 AN: 82544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5126

European-Non Finnish (NFE) AF: 0.000620 AC: 683 AN: 1101558

Other (OTH) AF: 0.000303 AC: 18 AN: 59504

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74420

African (AFR) AF: 0.000145 AC: 6 AN: 41518

American (AMR) AF: 0.000588 AC: 9 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 67986

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.000442 Hom.: 1

Bravo AF: 0.000370

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	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	not specified (1)
-	-	1	Perry syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.7
DANN	Benign	0.77
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=96/4	polymorphism

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: rs201078804; hg19: chr2-74598751;