NM_001723.7:c.7765A>G

Variant names:

• chr6-56615702-T-C
• rs150191284
• NM_001723.7:c.7765A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001723.7(DST):​c.7765A>G​(p.Ile2589Val) variant causes a missense change. The variant allele was found at a frequency of 0.0384 in 1,614,094 control chromosomes in the GnomAD database, including 1,495 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (76 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1419 hom.)
• Consequence: DST NM_001723.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.16
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066128075).
• BP6: Variant 6-56615702-T-C is Benign according to our data. Variant chr6-56615702-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 357543.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 = 0.0249 (3788/152358) while in subpopulation NFE AF = 0.0416 (2833/68026). AF 95% confidence interval is 0.0404. There are 76 homozygotes in GnomAd4. There are 1681 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 76 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001723.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	NM_001723.7	MANE Plus Clinical	c.7765A>G	p.Ile2589Val	missense	Exon 24 of 24	NP_001714.1
	DST	NM_001374736.1	MANE Select	c.4930-1218A>G		intron	N/A	NP_001361665.1
	DST	NM_001374734.1		c.4957-1218A>G		intron	N/A	NP_001361663.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.7765A>G	p.Ile2589Val	missense	Exon 24 of 24	ENSP00000359801.6
	DST	ENST00000680361.1	MANE Select	c.4930-1218A>G		intron	N/A	ENSP00000505098.1
	DST	ENST00000244364.10	TSL:1	c.3319-1218A>G		intron	N/A	ENSP00000244364.6

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3786 AN: 152240 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00803

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.00941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0251 AC: 6302 AN: 251224 AF XY: 0.0259

Gnomad AFR exome AF: 0.00751

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0470

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0398 AC: 58117 AN: 1461736 Hom.: 1419 Cov.: 34 AF XY: 0.0391 AC XY: 28416 AN XY: 727166

African (AFR) AF: 0.00639 AC: 214 AN: 33478

American (AMR) AF: 0.0136 AC: 607 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 1160 AN: 26132

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0219 AC: 1885 AN: 86254

European-Finnish (FIN) AF: 0.0133 AC: 711 AN: 53414

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.0462 AC: 51315 AN: 1111872

Other (OTH) AF: 0.0363 AC: 2191 AN: 60396

GnomAD4 genome AF: 0.0249 AC: 3788 AN: 152358 Hom.: 76 Cov.: 32 AF XY: 0.0226 AC XY: 1681 AN XY: 74512

African (AFR) AF: 0.00801 AC: 333 AN: 41598

American (AMR) AF: 0.0139 AC: 212 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 161 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5194

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4828

European-Finnish (FIN) AF: 0.00941 AC: 100 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0416 AC: 2833 AN: 68026

Other (OTH) AF: 0.0241 AC: 51 AN: 2112

Alfa AF: 0.0349 Hom.: 333

Bravo AF: 0.0244

TwinsUK AF: 0.0445 AC: 165

ALSPAC AF: 0.0506 AC: 195

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.0427 AC: 367

ExAC AF: 0.0239 AC: 2902

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.0374

EpiControl AF: 0.0362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 28, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary sensory and autonomic neuropathy type 6 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.98
Eigen	Benign	-0.048
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.83	T
PhyloP100		5.2
PROVEAN	Benign	0.070	N
REVEL	Benign	0.18
Sift	Benign	0.20	T
Sift4G	Benign	0.66	T
Polyphen		0.015	B
Vest4		0.036
ClinPred		0.0092	T
GERP RS		4.5
Mutation Taster		=96/4	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: rs150191284; hg19: chr6-56480500; COSMIC: COSV106081818; COSMIC: COSV106081818;