rs10484858

Variant names:

• chr6-56599214-T-C
• rs10484858
• NM_001374736.1:c.11695-505A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001374736.1(DST):​c.11695-505A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 151,896 control chromosomes in the GnomAD database, including 10,797 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (10797 hom., cov: 32)
• Consequence: DST NM_001374736.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.405
• Publications: 3 publications found

Genes affected

DST (HGNC:1090): (dystonin) This gene encodes a member of the plakin protein family of adhesion junction plaque proteins. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the full-length nature of some variants has not been defined. It has been reported that some isoforms are expressed in neural and muscle tissue, anchoring neural intermediate filaments to the actin cytoskeleton, and some isoforms are expressed in epithelial tissue, anchoring keratin-containing intermediate filaments to hemidesmosomes. Consistent with the expression, mice defective for this gene show skin blistering and neurodegeneration. [provided by RefSeq, Mar 2010]

DST Gene-Disease associations (from GenCC):

• hereditary sensory and autonomic neuropathy type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DST	NM_001374736.1	c.11695-505A>G		intron_variant	Intron 45 of 103	ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000680361.1	c.11695-505A>G		intron_variant	Intron 45 of 103		NM_001374736.1	ENSP00000505098.1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56447 AN: 151776 Hom.: 10784 Cov.: 32

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.394

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.372 AC: 56483 AN: 151896 Hom.: 10797 Cov.: 32 AF XY: 0.370 AC XY: 27435 AN XY: 74232

African (AFR) AF: 0.356 AC: 14750 AN: 41454

American (AMR) AF: 0.429 AC: 6541 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1637 AN: 3464

East Asian (EAS) AF: 0.263 AC: 1359 AN: 5176

South Asian (SAS) AF: 0.292 AC: 1408 AN: 4828

European-Finnish (FIN) AF: 0.312 AC: 3305 AN: 10578

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.384 AC: 26067 AN: 67854

Other (OTH) AF: 0.391 AC: 822 AN: 2102

Alfa AF: 0.378 Hom.: 5745

Bravo AF: 0.384

Asia WGS AF: 0.264 AC: 911 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.9
DANN	Benign	0.61
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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: rs10484858; hg19: chr6-56464012;