6-56552747-T-C

Position:

chr6-56552747-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DST. . Gene score misZ 2.2208 (greater than the threshold 3.09). Trascript score misZ 3.9149 (greater than threshold 3.09). GenCC has associacion of gene with hereditary sensory and autonomic neuropathy type 6, epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency.

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 id is 518377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56552747-T-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
DST	NM_001374736.1 linkuse as main transcript	c.16045A>G	p.Thr5349Ala	missense_variant	61/104	ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000680361.1 linkuse as main transcript	c.16045A>G	p.Thr5349Ala	missense_variant	61/104		NM_001374736.1	ENSP00000505098

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

GnomAD3 exomes

AF:

0.702

AC:

172988

AN:

246430

Hom.:

61189

AF XY:

0.701

AC XY:

93937

AN XY:

133936

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 SAS exome

AF:

0.666

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

Gnomad4 AFR exome

AF:

0.627

Gnomad4 AMR exome

AF:

0.722

Gnomad4 ASJ exome

AF:

0.599

Gnomad4 EAS exome

AF:

0.671

Gnomad4 SAS exome

AF:

0.663

Gnomad4 FIN exome

AF:

0.813

Gnomad4 NFE exome

AF:

0.711

Gnomad4 OTH exome

AF:

0.681

GnomAD4 genome

AF:

0.686

AC:

104259

AN:

152024

Hom.:

36032

Cov.:

AF XY:

0.689

AC XY:

51219

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.630

Gnomad4 AMR

AF:

0.687

Gnomad4 ASJ

AF:

0.589

Gnomad4 EAS

AF:

0.665

Gnomad4 SAS

AF:

0.657

Gnomad4 FIN

AF:

0.821

Gnomad4 NFE

AF:

0.710

Gnomad4 OTH

AF:

0.651

Alfa

AF:

0.699

Hom.:

67532

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over