chr2-74361590-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_004082.5(DCTN1):​c.3746C>G​(p.Thr1249Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. T1249I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCTN1 NM_004082.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.65

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-74361590-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.13768873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCTN1	NM_004082.5	c.3746C>G	p.Thr1249Ser	missense_variant	Exon 32 of 32	ENST00000628224.3	NP_004073.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCTN1	ENST00000628224.3	c.3746C>G	p.Thr1249Ser	missense_variant	Exon 32 of 32	5	NM_004082.5	ENSP00000487279.2
ENSG00000264324	ENST00000451608.2	n.485C>G		non_coding_transcript_exon_variant	Exon 5 of 39	5		ENSP00000416453.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.070	T;.;T;.;.;.;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	0.039
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T;T;T;T;T;T;.;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.84	L;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.23	N;N;.;.;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.59	T;T;.;.;T;T;T;T
Sift4G	Benign	0.82	T;T;T;T;T;T;T;T
Polyphen		0.38	B;.;.;B;.;.;.;.
Vest4		0.20
MutPred		0.25		Loss of methylation at K1247 (P = 0.102);.;.;.;.;.;.;.;
MVP		0.64
MPC		0.098
ClinPred		0.50	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr2-74588717;