rs568812456

Variant names:

• chr2-74365635-T-A
• rs568812456
• NM_004082.5:c.2909A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-74365635-T-A
• chr2-74365635-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004082.5(DCTN1):​c.2909A>T​(p.Asn970Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N970S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DCTN1 NM_004082.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.93
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40220404).

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.2909A>T	p.Asn970Ile	missense	Exon 25 of 32	NP_004073.2
	DCTN1	NM_001190837.2		c.2888A>T	p.Asn963Ile	missense	Exon 24 of 31	NP_001177766.1
	DCTN1	NM_001378991.1		c.2858A>T	p.Asn953Ile	missense	Exon 25 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.2909A>T	p.Asn970Ile	missense	Exon 25 of 32	ENSP00000487279.2
	DCTN1	ENST00000361874.8	TSL:1	c.2909A>T	p.Asn970Ile	missense	Exon 25 of 31	ENSP00000354791.4
	DCTN1	ENST00000409567.7	TSL:1	c.2849A>T	p.Asn950Ile	missense	Exon 22 of 28	ENSP00000386843.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251246 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74416

African (AFR) AF: 0.00 AC: 0 AN: 41518

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2110

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.074
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.29
Sift	Benign	0.28	T
Sift4G	Uncertain	0.024	D
Polyphen		0.39	B
Vest4		0.80
MutPred		0.23		Gain of catalytic residue at L975 (P = 0.077)
MVP		0.84
MPC		0.29
ClinPred		0.87	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.23
gMVP		0.48
Mutation Taster		=75/25	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: rs568812456; hg19: chr2-74592762;