6-56552747-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001374736.1(DST):c.16045A>G(p.Thr5349Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 1,610,246 control chromosomes in the GnomAD database, including 400,421 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T5349T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.69 ( 36032 hom., cov: 32)

Exomes 𝑓: 0.71 ( 364389 hom. )

Consequence

DST
NM_001374736.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.74

Publications

44 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.1254226E-7).

BP6

Variant 6-56552747-T-C is Benign according to our data. Variant chr6-56552747-T-C is described in ClinVar as Benign. ClinVar VariationId is 518377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DST	NM_001374736.1 link	c.16045A>G	p.Thr5349Ala	missense_variant	Exon 61 of 104	ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000680361.1 link	c.16045A>G	p.Thr5349Ala	missense_variant	Exon 61 of 104		NM_001374736.1	ENSP00000505098.1		A0A7P0T890

Frequencies

GnomAD3 genomes

AF:

0.686

AC:

104162

AN:

151906

Hom.:

35990

Cov.:

show subpopulations

Gnomad AFR

AF:

0.630

Gnomad AMI

AF:

0.566

Gnomad AMR

AF:

0.687

Gnomad ASJ

AF:

0.589

Gnomad EAS

AF:

0.663

Gnomad SAS

AF:

0.656

Gnomad FIN

AF:

0.821

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.710

Gnomad OTH

AF:

0.648

GnomAD2 exomes

AF:

0.702

AC:

172988

AN:

246430

AF XY:

0.701

show subpopulations

Gnomad AFR exome

AF:

0.631

Gnomad AMR exome

AF:

0.726

Gnomad ASJ exome

AF:

0.594

Gnomad EAS exome

AF:

0.653

Gnomad FIN exome

AF:

0.818

Gnomad NFE exome

AF:

0.712

Gnomad OTH exome

AF:

0.685

GnomAD4 exome

AF:

0.706

AC:

1029058

AN:

1458222

Hom.:

364389

Cov.:

AF XY:

0.704

AC XY:

511078

AN XY:

725554

show subpopulations

African (AFR)

AF:

0.627

AC:

20997

AN:

33476

American (AMR)

AF:

0.722

AC:

32298

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.599

AC:

15665

AN:

26134

East Asian (EAS)

AF:

0.671

AC:

26646

AN:

39692

South Asian (SAS)

AF:

0.663

AC:

57149

AN:

86254

European-Finnish (FIN)

AF:

0.813

AC:

40736

AN:

50092

Middle Eastern (MID)

AF:

0.622

AC:

3586

AN:

5768

European-Non Finnish (NFE)

AF:

0.711

AC:

790876

AN:

1111750

Other (OTH)

AF:

0.681

AC:

41105

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

19332

38664

57996

77328

96660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19828

39656

59484

79312

99140

<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:

0.686

AC:

104259

AN:

152024

Hom.:

36032

Cov.:

AF XY:

0.689

AC XY:

51219

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.630

AC:

26082

AN:

41420

American (AMR)

AF:

0.687

AC:

10496

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.589

AC:

2043

AN:

3466

East Asian (EAS)

AF:

0.665

AC:

3437

AN:

5172

South Asian (SAS)

AF:

0.657

AC:

3167

AN:

4824

European-Finnish (FIN)

AF:

0.821

AC:

8699

AN:

10594

Middle Eastern (MID)

AF:

0.592

AC:

174

AN:

294

European-Non Finnish (NFE)

AF:

0.710

AC:

48278

AN:

67972

Other (OTH)

AF:

0.651

AC:

1370

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1671

3343

5014

6686

8357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

826

1652

2478

3304

4130

<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:

0.697

Hom.:

131492

Bravo

AF:

0.670

TwinsUK

AF:

0.707

AC:

2622

ALSPAC

AF:

0.707

AC:

2724

ESP6500AA

AF:

0.642

AC:

2419

ESP6500EA

AF:

0.702

AC:

5792

ExAC

AF:

0.703

AC:

84931

Asia WGS

AF:

0.663

AC:

2308

AN:

3478

EpiCase

AF:

0.698

EpiControl

AF:

0.694

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary sensory and autonomic neuropathy type 6

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Nov 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0026

.;.;.;.;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.80

T;T;T;T;T

MetaRNN

Benign

7.1e-7

T;T;T;T;T

MetaSVM

Benign

-0.97

PhyloP100

2.7

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.97

N;N;.;N;N

REVEL

Benign

0.074

Sift

Benign

1.0

T;T;.;T;T

Polyphen

0.0010

B;.;.;.;.

Vest4

0.052

MPC

0.12

ClinPred

0.0079

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.085

Mutation Taster

=98/2

polymorphism (auto)

(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