6-56640508-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001374736.1(DST):c.2125A>G(p.Met709Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,613,620 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M709L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 1 hom. )

Consequence

DST
NM_001374736.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 3.24

Publications

4 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014545411).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374736.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DST	NM_001374736.1	MANE Select	c.2125A>G	p.Met709Val	missense	Exon 18 of 104	NP_001361665.1
DST	NM_001723.7	MANE Plus Clinical	c.514A>G	p.Met172Val	missense	Exon 4 of 24	NP_001714.1
DST	NM_001374734.1		c.2152A>G	p.Met718Val	missense	Exon 18 of 103	NP_001361663.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DST	ENST00000680361.1	MANE Select	c.2125A>G	p.Met709Val	missense	Exon 18 of 104	ENSP00000505098.1
DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.514A>G	p.Met172Val	missense	Exon 4 of 24	ENSP00000359801.6
DST	ENST00000244364.10	TSL:1	c.514A>G	p.Met172Val	missense	Exon 4 of 84	ENSP00000244364.6

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000565

AC:

142

AN:

251440

AF XY:

0.000552

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000572

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000697

AC:

1019

AN:

1461288

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

498

AN XY:

727006

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33472

American (AMR)

AF:

0.000850

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00390

AC:

102

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000162

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000742

AC:

825

AN:

1111438

Other (OTH)

AF:

0.000613

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

120

180

240

300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.000387

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41576

American (AMR)

AF:

0.000588

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

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:

0.000746

Hom.:

Bravo

AF:

0.000548

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000445

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jun 04, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 26, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Reported using the transcript encoding the epithelial isoform of the gene

Inborn genetic diseases

Uncertain:1

Nov 16, 2023

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.

Hereditary sensory and autonomic neuropathy type 6

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

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

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DST-related disorder

Benign:1

Apr 24, 2024

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.033

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

M_CAP

Benign

0.015

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.71

PhyloP100

3.2

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.1

REVEL

Benign

0.23

Sift

Benign

0.11

Sift4G

Benign

0.27

Polyphen

0.098

Vest4

0.23

MVP

0.65

MPC

0.12

ClinPred

0.020

GERP RS

2.1

gMVP

0.80

Mutation Taster

=82/18

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over