2-74361478-G-A

Variant names:

• chr2-74361478-G-A
• rs11555696
• NM_004082.5:c.*21C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004082.5(DCTN1):​c.*21C>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 0.0275 in 1,613,896 control chromosomes in the GnomAD database, including 704 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (53 hom., cov: 32)
  • Exomes 𝑓: 0.028 (651 hom.)
• Consequence: DCTN1 NM_004082.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.447

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-74361478-G-A is Benign according to our data. Variant chr2-74361478-G-A is described in ClinVar as [Benign]. Clinvar id is 337066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0223 (3393/152296) while in subpopulation NFE AF= 0.0315 (2141/68020). AF 95% confidence interval is 0.0304. There are 53 homozygotes in gnomad4. There are 1674 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3393 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCTN1	NM_004082.5	c.*21C>T		3_prime_UTR_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	c.*21C>T		3_prime_UTR_variant	Exon 32 of 32	5	NM_004082.5	ENSP00000487279.2
ENSG00000264324	ENST00000451608.2	n.*21C>T		non_coding_transcript_exon_variant	Exon 5 of 39	5		ENSP00000416453.2
ENSG00000264324	ENST00000451608.2	n.*21C>T		3_prime_UTR_variant	Exon 5 of 39	5		ENSP00000416453.2

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3397 AN: 152178 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.00540

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0333

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0335

GnomAD3 exomes AF: 0.0227 AC: 5684 AN: 250826 Hom.: 81 AF XY: 0.0226 AC XY: 3063 AN XY: 135598

Gnomad AFR exome AF: 0.00506

Gnomad AMR exome AF: 0.0200

Gnomad ASJ exome AF: 0.0335

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00572

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0315

Gnomad OTH exome AF: 0.0282

GnomAD4 exome AF: 0.0281 AC: 41020 AN: 1461600 Hom.: 651 Cov.: 31 AF XY: 0.0275 AC XY: 20025 AN XY: 727088

Gnomad4 AFR exome AF: 0.00475

Gnomad4 AMR exome AF: 0.0214

Gnomad4 ASJ exome AF: 0.0305

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00560

Gnomad4 FIN exome AF: 0.0292

Gnomad4 NFE exome AF: 0.0318

Gnomad4 OTH exome AF: 0.0261

GnomAD4 genome AF: 0.0223 AC: 3393 AN: 152296 Hom.: 53 Cov.: 32 AF XY: 0.0225 AC XY: 1674 AN XY: 74454

Gnomad4 AFR AF: 0.00539

Gnomad4 AMR AF: 0.0274

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.0333

Gnomad4 NFE AF: 0.0315

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0319 Hom.: 81

Bravo AF: 0.0221

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Perry syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.79
CADD	Benign	13
DANN	Benign	0.75

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: rs11555696; hg19: chr2-74588605;