2-74363626-C-T

Variant names:

• chr2-74363626-C-T
• rs376996779
• NM_004082.5:c.3199G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_004082.5(DCTN1):​c.3199G>A​(p.Glu1067Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000342 in 1,461,480 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DCTN1 NM_004082.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.87

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]

ENSG00000264324 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCTN1	NM_004082.5	c.3199G>A	p.Glu1067Lys	missense_variant, splice_region_variant	Exon 27 of 32	ENST00000628224.3	NP_004073.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCTN1	ENST00000628224.3	c.3199G>A	p.Glu1067Lys	missense_variant, splice_region_variant	Exon 27 of 32	5	NM_004082.5	ENSP00000487279.2
ENSG00000264324	ENST00000451608.2	n.-249G>A		upstream_gene_variant		5		ENSP00000416453.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250388 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135310

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 SAS exome AF: 0.0000657

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461480 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726972

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Benign	0.87
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.1	L;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.26	N;N;.
REVEL	Benign	0.19
Sift	Benign	0.71	T;T;.
Sift4G	Benign	0.83	T;T;T
Polyphen		0.46	P;.;B
Vest4		0.59
MutPred		0.27		Gain of ubiquitination at E1067 (P = 0.0054);.;.;
MVP		0.80
MPC		0.12
ClinPred		0.41	T
GERP RS		4.7
Varity_R		0.28
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs376996779; hg19: chr2-74590753;