NM_004082.5:c.1217G>C

Variant names:

• chr2-74370256-C-G
• rs1040712616
• NM_004082.5:c.1217G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004082.5(DCTN1):​c.1217G>C​(p.Arg406Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R406K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCTN1 NM_004082.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.98
• 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: 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCTN1	NM_004082.5	c.1217G>C	p.Arg406Thr	missense_variant	Exon 12 of 32	ENST00000628224.3	NP_004073.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCTN1	ENST00000628224.3	c.1217G>C	p.Arg406Thr	missense_variant	Exon 12 of 32	5	NM_004082.5	ENSP00000487279.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.19	T;.;T;.;.;.;T;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;.;D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.69	N;.;.;.;.;.;.;.
PhyloP100		6.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.5	N;N;.;.;N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.23	T;T;.;.;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T;T;T;T
Polyphen		0.98	D;.;.;B;.;.;.;.
Vest4		0.73
MutPred		0.20		Loss of MoRF binding (P = 0.018);.;.;.;.;.;.;.;
MVP		0.91
MPC		1.9
ClinPred		0.85	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.46
Mutation Taster		=53/47	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: rs1040712616; hg19: chr2-74597383;