rs143259402

Variant names:

• chr6-56640063-G-A
• rs143259402
• NM_001374736.1:c.2491-6C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-56640063-G-A
• chr6-56640063-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001374736.1(DST):​c.2491-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,613,946 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0059 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (5 hom.)
• Consequence: DST NM_001374736.1 splice_region, intron
• Scores: Splicing: ADA: 0.00001333
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.21
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-56640063-G-A is Benign according to our data. Variant chr6-56640063-G-A is described in ClinVar as Benign. ClinVar VariationId is 541486.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00586 (892/152210) while in subpopulation AFR AF = 0.0205 (852/41534). AF 95% confidence interval is 0.0194. There are 4 homozygotes in GnomAd4. There are 430 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DST	NM_001374736.1	c.2491-6C>T		splice_region_variant, intron_variant	Intron 18 of 103	ENST00000680361.1	NP_001361665.1
DST	NM_001723.7	c.880-6C>T		splice_region_variant, intron_variant	Intron 4 of 23	ENST00000370765.11	NP_001714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000680361.1	c.2491-6C>T		splice_region_variant, intron_variant	Intron 18 of 103		NM_001374736.1	ENSP00000505098.1
DST	ENST00000370765.11	c.880-6C>T		splice_region_variant, intron_variant	Intron 4 of 23	1	NM_001723.7	ENSP00000359801.6

Frequencies

GnomAD3 genomes AF: 0.00583 AC: 886 AN: 152092 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00152 AC: 380 AN: 250188 AF XY: 0.00107

Gnomad AFR exome AF: 0.0221

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000558 AC: 815 AN: 1461736 Hom.: 5 Cov.: 33 AF XY: 0.000455 AC XY: 331 AN XY: 727166

African (AFR) AF: 0.0201 AC: 673 AN: 33476

American (AMR) AF: 0.000716 AC: 32 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111936

Other (OTH) AF: 0.000994 AC: 60 AN: 60386

GnomAD4 genome AF: 0.00586 AC: 892 AN: 152210 Hom.: 4 Cov.: 32 AF XY: 0.00578 AC XY: 430 AN XY: 74402

African (AFR) AF: 0.0205 AC: 852 AN: 41534

American (AMR) AF: 0.00157 AC: 24 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68018

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00307 Hom.: 3

Bravo AF: 0.00652

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DST-related disorder Benign:1

Jun 05, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.3
DANN	Benign	0.46
PhyloP100		1.2
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
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: rs143259402; hg19: chr6-56504861;