rs55862001

Variant names:

• chr2-74371596-T-C
• rs55862001
• NM_004082.5:c.586A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-74371596-T-C
• chr2-74371596-T-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004082.5(DCTN1):​c.586A>G​(p.Ile196Val) variant causes a missense change. The variant allele was found at a frequency of 0.00614 in 1,588,362 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I196M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (37 hom.)
• Consequence: DCTN1 NM_004082.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 4.50
• Publications: 15 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054398477).
• BP6: Variant 2-74371596-T-C is Benign according to our data. Variant chr2-74371596-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 337096.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00448 (681/151948) while in subpopulation NFE AF = 0.00671 (456/67930). AF 95% confidence interval is 0.0062. There are 3 homozygotes in GnomAd4. There are 276 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 681 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.586A>G	p.Ile196Val	missense	Exon 8 of 32	NP_004073.2
	DCTN1	NM_001190837.2		c.565A>G	p.Ile189Val	missense	Exon 7 of 31	NP_001177766.1	Q14203-6
	DCTN1	NM_001378991.1		c.535A>G	p.Ile179Val	missense	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.586A>G	p.Ile196Val	missense	Exon 8 of 32	ENSP00000487279.2	Q14203-1
	DCTN1	ENST00000361874.8	TSL:1	c.586A>G	p.Ile196Val	missense	Exon 8 of 31	ENSP00000354791.4	A0A804CDA6
	DCTN1	ENST00000409567.7	TSL:1	c.526A>G	p.Ile176Val	missense	Exon 5 of 28	ENSP00000386843.3	Q14203-4

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 681 AN: 151830 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00671

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00460 AC: 948 AN: 205926 AF XY: 0.00438

Gnomad AFR exome AF: 0.000630

Gnomad AMR exome AF: 0.00391

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00615

Gnomad OTH exome AF: 0.00574

GnomAD4 exome AF: 0.00632 AC: 9075 AN: 1436414 Hom.: 37 Cov.: 32 AF XY: 0.00624 AC XY: 4444 AN XY: 711960

African (AFR) AF: 0.000663 AC: 22 AN: 33178

American (AMR) AF: 0.00449 AC: 182 AN: 40526

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 517 AN: 25564

East Asian (EAS) AF: 0.00 AC: 0 AN: 38774

South Asian (SAS) AF: 0.000899 AC: 74 AN: 82330

European-Finnish (FIN) AF: 0.00141 AC: 73 AN: 51680

Middle Eastern (MID) AF: 0.00395 AC: 20 AN: 5064

European-Non Finnish (NFE) AF: 0.00703 AC: 7732 AN: 1099948

Other (OTH) AF: 0.00767 AC: 455 AN: 59350

GnomAD4 genome AF: 0.00448 AC: 681 AN: 151948 Hom.: 3 Cov.: 32 AF XY: 0.00372 AC XY: 276 AN XY: 74286

African (AFR) AF: 0.00118 AC: 49 AN: 41442

American (AMR) AF: 0.00327 AC: 50 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4782

European-Finnish (FIN) AF: 0.00274 AC: 29 AN: 10580

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00671 AC: 456 AN: 67930

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00669 Hom.: 14

Bravo AF: 0.00483

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00768 AC: 66

ExAC AF: 0.00356 AC: 430

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	1	1	Perry syndrome (2)
-	1	-	Amyotrophic lateral sclerosis (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.76	N
PhyloP100		4.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.11
Sift	Benign	0.54	T
Sift4G	Benign	0.81	T
Polyphen		0.0010	B
Vest4		0.32
MVP		0.75
MPC		0.49
ClinPred		0.0075	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.024
gMVP		0.16
Mutation Taster		=97/3	polymorphism

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: rs55862001; hg19: chr2-74598723;