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rs1130484

chr2-74366801-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004082.5(DCTN1):c.2448A>G(p.Ala816=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00893 in 1,614,236 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 57 hom., cov: 32)
Exomes 𝑓: 0.0080 ( 98 hom. )

Consequence

DCTN1
NM_004082.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.97
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-74366801-T-C is Benign according to our data. Variant chr2-74366801-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 259235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74366801-T-C is described in Lovd as [Benign]. Variant chr2-74366801-T-C is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-2.97 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0177 (2696/152342) while in subpopulation AFR AF= 0.0436 (1814/41572). AF 95% confidence interval is 0.042. There are 57 homozygotes in gnomad4. There are 1290 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 2687 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DCTN1NM_004082.5 linkuse as main transcriptc.2448A>G p.Ala816= synonymous_variant 21/32 ENST00000628224.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DCTN1ENST00000628224.3 linkuse as main transcriptc.2448A>G p.Ala816= synonymous_variant 21/325 NM_004082.5 A1Q14203-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0177
AC:
2687
AN:
152224
Hom.:
57
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0435
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.0137
Gnomad ASJ
AF:
0.0253
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0114
Gnomad FIN
AF:
0.00207
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.00692
Gnomad OTH
AF:
0.0148
GnomAD3 exomes
AF:
0.0101
AC:
2539
AN:
251492
Hom.:
36
AF XY:
0.0100
AC XY:
1365
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.0450
Gnomad AMR exome
AF:
0.00411
Gnomad ASJ exome
AF:
0.0306
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0140
Gnomad FIN exome
AF:
0.00323
Gnomad NFE exome
AF:
0.00695
Gnomad OTH exome
AF:
0.0106
GnomAD4 exome
AF:
0.00801
AC:
11714
AN:
1461894
Hom.:
98
Cov.:
33
AF XY:
0.00803
AC XY:
5839
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0480
Gnomad4 AMR exome
AF:
0.00467
Gnomad4 ASJ exome
AF:
0.0279
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0145
Gnomad4 FIN exome
AF:
0.00344
Gnomad4 NFE exome
AF:
0.00634
Gnomad4 OTH exome
AF:
0.0101
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0177
AC:
2696
AN:
152342
Hom.:
57
Cov.:
32
AF XY:
0.0173
AC XY:
1290
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.0436
Gnomad4 AMR
AF:
0.0137
Gnomad4 ASJ
AF:
0.0253
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0114
Gnomad4 FIN
AF:
0.00207
Gnomad4 NFE
AF:
0.00692
Gnomad4 OTH
AF:
0.0147
Alfa
AF:
0.0135
Hom.:
9
Bravo
AF:
0.0195
Asia WGS
AF:
0.00866
AC:
30
AN:
3478
EpiCase
AF:
0.00774
EpiControl
AF:
0.00551

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsFeb 10, 2021- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 17, 2021- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 06, 2023- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Neuronopathy, distal hereditary motor, type 7B Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Neuronopathy, distal hereditary motor, type 7B;C1862939:Amyotrophic lateral sclerosis type 1;C1868594:Perry syndrome Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Perry syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
Cadd
Benign
5.4
Dann
Benign
0.47
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.9

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1130484; hg19: chr2-74593928; COSMIC: COSV62621026; COSMIC: COSV62621026; API