rs72466496

Variant names:

• chr2-74361590-G-A
• rs72466496
• NM_004082.5:c.3746C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-74361590-G-A
• chr2-74361590-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004082.5(DCTN1):​c.3746C>T​(p.Thr1249Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00473 in 1,614,110 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1249T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (29 hom.)
• Consequence: DCTN1 NM_004082.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:11 O:1
• Conservation: PhyloP100: 4.65
• Publications: 34 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

ENSG00000264324 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007178724).
• BP6: Variant 2-74361590-G-A is Benign according to our data. Variant chr2-74361590-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 8402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00282 (430/152224) while in subpopulation NFE AF = 0.00491 (334/68008). AF 95% confidence interval is 0.00448. There are 2 homozygotes in GnomAd4. There are 214 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 430 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCTN1	NM_004082.5	MANE Select	c.3746C>T	p.Thr1249Ile	missense	Exon 32 of 32	NP_004073.2
	DCTN1	NM_001190837.2		c.3725C>T	p.Thr1242Ile	missense	Exon 31 of 31	NP_001177766.1
	DCTN1	NM_001378991.1		c.3695C>T	p.Thr1232Ile	missense	Exon 32 of 32	NP_001365920.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCTN1	ENST00000628224.3	TSL:5 MANE Select	c.3746C>T	p.Thr1249Ile	missense	Exon 32 of 32	ENSP00000487279.2
	DCTN1	ENST00000361874.8	TSL:1	c.3731C>T	p.Thr1244Ile	missense	Exon 31 of 31	ENSP00000354791.4
	DCTN1	ENST00000409567.7	TSL:1	c.3671C>T	p.Thr1224Ile	missense	Exon 28 of 28	ENSP00000386843.3

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 430 AN: 152106 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00288 AC: 725 AN: 251428 AF XY: 0.00297

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00496

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00492 AC: 7197 AN: 1461886 Hom.: 29 Cov.: 31 AF XY: 0.00484 AC XY: 3522 AN XY: 727248

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.00110 AC: 49 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26136

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

South Asian (SAS) AF: 0.00212 AC: 183 AN: 86258

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00600 AC: 6668 AN: 1112008

Other (OTH) AF: 0.00354 AC: 214 AN: 60396

GnomAD4 genome AF: 0.00282 AC: 430 AN: 152224 Hom.: 2 Cov.: 32 AF XY: 0.00287 AC XY: 214 AN XY: 74438

African (AFR) AF: 0.000843 AC: 35 AN: 41540

American (AMR) AF: 0.00281 AC: 43 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00491 AC: 334 AN: 68008

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00408 Hom.: 4

Bravo AF: 0.00294

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00304 AC: 369

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	1	1	Perry syndrome (2)
-	-	1	Amyotrophic lateral sclerosis type 1 (1)
-	-	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)
-	-	-	Amyotrophic lateral sclerosis, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.38
Sift	Benign	0.033	D
Sift4G	Benign	0.13	T
Polyphen		0.27	B
Vest4		0.68
MVP		0.68
MPC		0.12
ClinPred		0.0099	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.078
gMVP		0.54
Mutation Taster		=100/0	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: rs72466496; hg19: chr2-74588717;