chr2-74361388-G-A

Variant names:

• chr2-74361388-G-A
• rs1673974256
• NM_004082.5:c.*111C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004082.5(DCTN1):​c.*111C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,345,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: DCTN1 NM_004082.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.0940
• Publications: 0 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• distal hereditary motor neuropathy type 7

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000264324 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCTN1	NM_004082.5	MANE Select	c.*111C>T		3_prime_UTR	Exon 32 of 32	NP_004073.2
	DCTN1	NM_001190837.2		c.*111C>T		3_prime_UTR	Exon 31 of 31	NP_001177766.1	Q14203-6
	DCTN1	NM_001378991.1		c.*111C>T		3_prime_UTR	Exon 32 of 32	NP_001365920.1	A0A7P0Z4C3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCTN1	ENST00000628224.3	TSL:5 MANE Select	c.*111C>T		3_prime_UTR	Exon 32 of 32	ENSP00000487279.2	Q14203-1
	DCTN1	ENST00000361874.8	TSL:1	c.*111C>T		3_prime_UTR	Exon 31 of 31	ENSP00000354791.4	A0A804CDA6
	DCTN1	ENST00000409240.5	TSL:1	c.*111C>T		3_prime_UTR	Exon 28 of 28	ENSP00000386406.1	Q14203-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1345960 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 672386

African (AFR) AF: 0.00 AC: 0 AN: 31286

American (AMR) AF: 0.00 AC: 0 AN: 41032

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25072

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38306

South Asian (SAS) AF: 0.00 AC: 0 AN: 81036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1023966

Other (OTH) AF: 0.00 AC: 0 AN: 56608

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neuronopathy, distal hereditary motor, type 7B (1)
-	1	-	Perry syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		0.094
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1673974256; hg19: chr2-74588515;