rs766585070

Variant names:

• chr2-74366610-G-A
• rs766585070
• NM_004082.5:c.2477C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-74366610-G-A
• chr2-74366610-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_004082.5(DCTN1):​c.2477C>T​(p.Thr826Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000416 in 1,612,144 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T826T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: DCTN1 NM_004082.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 5.38
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000438 (64/1459882) while in subpopulation AFR AF = 0.0000597 (2/33480). AF 95% confidence interval is 0.0000389. There are 0 homozygotes in GnomAdExome4. There are 39 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 64 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.2477C>T	p.Thr826Met	missense	Exon 22 of 32	NP_004073.2
	DCTN1	NM_001190837.2		c.2456C>T	p.Thr819Met	missense	Exon 21 of 31	NP_001177766.1
	DCTN1	NM_001378991.1		c.2426C>T	p.Thr809Met	missense	Exon 22 of 32	NP_001365920.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCTN1	ENST00000628224.3	TSL:5 MANE Select	c.2477C>T	p.Thr826Met	missense	Exon 22 of 32	ENSP00000487279.2
	DCTN1	ENST00000361874.8	TSL:1	c.2477C>T	p.Thr826Met	missense	Exon 22 of 31	ENSP00000354791.4
	DCTN1	ENST00000409567.7	TSL:1	c.2417C>T	p.Thr806Met	missense	Exon 19 of 28	ENSP00000386843.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152262 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000481 AC: 12 AN: 249222 AF XY: 0.0000593

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1459882 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 39 AN XY: 726322

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74390

African (AFR) AF: 0.0000241 AC: 1 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Neuronopathy, distal hereditary motor, type 7B;C1862939:Amyotrophic lateral sclerosis type 1;C1868594:Perry syndrome (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.59
MutPred		0.47		Loss of phosphorylation at T826 (P = 0.2053)
MVP		0.96
MPC		0.38
ClinPred		0.13	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.43
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs766585070; hg19: chr2-74593737; COSMIC: COSV62619871; COSMIC: COSV62619871;