rs115689748

Variant names:

• chr2-74362665-G-A
• rs115689748
• NM_004082.5:c.3594C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-74362665-G-A
• chr2-74362665-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_004082.5(DCTN1):​c.3594C>T​(p.Thr1198Thr) variant causes a synonymous change. The variant allele was found at a frequency of 0.000417 in 1,613,874 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (3 hom.)
• Consequence: DCTN1 NM_004082.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.11
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 2-74362665-G-A is Benign according to our data. Variant chr2-74362665-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 337070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00234 (356/152290) while in subpopulation AFR AF = 0.00818 (340/41554). AF 95% confidence interval is 0.00747. There are 4 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 356 AD gene.

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.3594C>T	p.Thr1198Thr	synonymous	Exon 30 of 32	NP_004073.2
	DCTN1	NM_001190837.2		c.3573C>T	p.Thr1191Thr	synonymous	Exon 29 of 31	NP_001177766.1	Q14203-6
	DCTN1	NM_001378991.1		c.3543C>T	p.Thr1181Thr	synonymous	Exon 30 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.3594C>T	p.Thr1198Thr	synonymous	Exon 30 of 32	ENSP00000487279.2	Q14203-1
	DCTN1	ENST00000361874.8	TSL:1	c.3579C>T	p.Thr1193Thr	synonymous	Exon 29 of 31	ENSP00000354791.4	A0A804CDA6
	DCTN1	ENST00000409567.7	TSL:1	c.3519C>T	p.Thr1173Thr	synonymous	Exon 26 of 28	ENSP00000386843.3	Q14203-4

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152172 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000621 AC: 156 AN: 251054 AF XY: 0.000523

Gnomad AFR exome AF: 0.00783

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000217 AC: 317 AN: 1461584 Hom.: 3 Cov.: 31 AF XY: 0.000195 AC XY: 142 AN XY: 727098

African (AFR) AF: 0.00699 AC: 234 AN: 33470

American (AMR) AF: 0.000492 AC: 22 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39694

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111920

Other (OTH) AF: 0.000464 AC: 28 AN: 60368

GnomAD4 genome AF: 0.00234 AC: 356 AN: 152290 Hom.: 4 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74474

African (AFR) AF: 0.00818 AC: 340 AN: 41554

American (AMR) AF: 0.000850 AC: 13 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00254

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronopathy, distal hereditary motor, type 7B (1)
-	-	1	Neuronopathy, distal hereditary motor, type 7B;C1862939:Amyotrophic lateral sclerosis type 1;C1868594:Perry syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Perry syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs115689748; hg19: chr2-74589792; COSMIC: COSV62619608; COSMIC: COSV62619608;