rs570863800

Variant names:

• chr2-74370344-T-A
• NM_004082.5:c.1129A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-74370344-T-A
• chr2-74370344-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004082.5(DCTN1):​c.1129A>T​(p.Met377Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DCTN1 NM_004082.5 missense, splice_region
• Scores: Splicing: ADA: 0.1313
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28421873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCTN1	NM_004082.5	c.1129A>T	p.Met377Leu	missense_variant, splice_region_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.1129A>T	p.Met377Leu	missense_variant, splice_region_variant	Exon 12 of 32	5	NM_004082.5	ENSP00000487279.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461710 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727184

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.19	T;.;T;.;.;.;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.027
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;.;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.49	N;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.1	N;N;.;.;N;N;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.14	T;T;.;.;T;T;T;T
Sift4G	Benign	0.88	T;T;T;T;T;T;T;T
Polyphen		0.52	P;.;.;B;.;.;.;.
Vest4		0.61
MutPred		0.33		Loss of MoRF binding (P = 0.1266);.;.;.;.;.;.;.;
MVP		0.66
MPC		0.58
ClinPred		0.81	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.13
dbscSNV1_RF	Benign	0.42
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-74597471;