2-74361332-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004082.5(DCTN1):c.*167C>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 0.0017 in 960,446 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (2 hom.)
• Consequence: DCTN1 NM_004082.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.415

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-74361332-G-A is Benign according to our data. Variant chr2-74361332-G-A is described in ClinVar as [Benign]. Clinvar id is 337062.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00143 (218/152234) while in subpopulation NFE AF= 0.0026 (177/68010). AF 95% confidence interval is 0.00229. There are 1 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 218 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCTN1	NM_004082.5	c.*167C>T		3_prime_UTR_variant	32/32	ENST00000628224.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCTN1	ENST00000628224.3	c.*167C>T		3_prime_UTR_variant	32/32	5	NM_004082.5	A1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152116 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00260

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00118 AC: 171 AN: 144638 Hom.: 0 AF XY: 0.00127 AC XY: 98 AN XY: 77274

Gnomad AFR exome AF: 0.000267

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000437

Gnomad FIN exome AF: 0.000341

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00162

GnomAD4 exome AF: 0.00175 AC: 1413 AN: 808212 Hom.: 2 Cov.: 11 AF XY: 0.00162 AC XY: 679 AN XY: 420186

Gnomad4 AFR exome AF: 0.000391

Gnomad4 AMR exome AF: 0.00129

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000304

Gnomad4 SAS exome AF: 0.0000745

Gnomad4 FIN exome AF: 0.000432

Gnomad4 NFE exome AF: 0.00229

Gnomad4 OTH exome AF: 0.00178

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152234 Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74428

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00260

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000719 Hom.: 0

Bravo AF: 0.00138

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronopathy, distal hereditary motor, type 7B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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. -

Perry syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This 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	-0.88
Cadd	Benign	1.7
Dann	Benign	0.51
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

Publications

LitVar

Other links and lift over

dbSNP: rs142053202; hg19: chr2-74588459;