rs34767818

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001723.7(DST):c.3336G>C(p.Glu1112Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00492 in 1,613,844 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 26 hom. )

Consequence

DST
NM_001723.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:4

Conservation

PhyloP100: 0.498

Publications

7 publications found

Variant links:

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

DST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006155789).

BP6

Variant 6-56620698-C-G is Benign according to our data. Variant chr6-56620698-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 357589.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00338 (515/152286) while in subpopulation NFE AF = 0.00564 (384/68026). AF 95% confidence interval is 0.00518. There are 1 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DST	NM_001723.7 link	c.3336G>C	p.Glu1112Asp	missense_variant	Exon 23 of 24	ENST00000370765.11	NP_001714.1	Q03001-3
DST	NM_001374736.1 link	c.4929+3832G>C		intron_variant	Intron 36 of 103	ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000370765.11 link	c.3336G>C	p.Glu1112Asp	missense_variant	Exon 23 of 24	1	NM_001723.7	ENSP00000359801.6		Q03001-3
DST	ENST00000680361.1 link	c.4929+3832G>C		intron_variant	Intron 36 of 103		NM_001374736.1	ENSP00000505098.1		A0A7P0T890

Frequencies

GnomAD3 genomes

AF:

0.00338

AC:

514

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00564

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00347

AC:

868

AN:

250036

AF XY:

0.00354

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000555

Gnomad NFE exome

AF:

0.00607

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00508

AC:

7428

AN:

1461558

Hom.:

Cov.:

AF XY:

0.00498

AC XY:

3619

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33478

American (AMR)

AF:

0.00197

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00170

AC:

147

AN:

86254

European-Finnish (FIN)

AF:

0.000713

AC:

AN:

53310

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00612

AC:

6806

AN:

1111804

Other (OTH)

AF:

0.00439

AC:

265

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

360

720

1079

1439

1799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

244

488

732

976

1220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00338

AC:

515

AN:

152286

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

203

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

41550

American (AMR)

AF:

0.00360

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00564

AC:

384

AN:

68026

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

127

159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00519

Hom.:

Bravo

AF:

0.00381

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.00325

AC:

395

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00610

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DST: BP4, BS2 -

Oct 14, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 29, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Hereditary sensory and autonomic neuropathy type 6

Uncertain:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Multiple sclerosis

Pathogenic:1

Jun 10, 2024

Department of Molecular Biology and Genetics, Acibadem University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Inborn genetic diseases

Uncertain:1

Nov 02, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Unlikely to be causative of DST-related sensory and autonomic neuropathy (AR) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Dec 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DST c.3336G>C (p.Glu1112Asp) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0035 in 250036 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in DST causing Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency phenotype (0.0011). c.3336G>C has been reported in the literature in an individual affected with progressive neuropathies, muscle weakness, Raynauds phenomenon, scleroderma syncope and hypermobility, without strong evidence for causality (Bloss_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25790160). ClinVar contains an entry for this variant (Variation ID: 357589). Based on the evidence outlined above, the variant was classified as likely benign. -

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DST-related disorder

Benign:1

Mar 12, 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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.51

M_CAP

Benign

0.0046

MetaRNN

Benign

0.0062

MetaSVM

Benign

-1.0

PhyloP100

0.50

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.070

Sift

Benign

0.45

Sift4G

Uncertain

0.057

Polyphen

0.99

Vest4

0.50

MutPred

0.17

Loss of methylation at K1108 (P = 0.1648);

MVP

0.38

ClinPred

0.024

GERP RS

4.4

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over