rs151271595

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001374736.1(DST):c.2350C>G(p.Pro784Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,614,108 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 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 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 21 hom. )

Consequence

DST
NM_001374736.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.441

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:

DST (HGNC:):

DST links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 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=0.0032327473).

BP6

Variant 6-56640283-G-C is Benign according to our data. Variant chr6-56640283-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 357616.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}. Variant chr6-56640283-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00275 (4022/1461852) while in subpopulation SAS AF= 0.0102 (877/86258). AF 95% confidence interval is 0.00961. There are 21 homozygotes in gnomad4_exome. There are 2154 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DST	NM_001374736.1 linkuse as main transcript	c.2350C>G	p.Pro784Ala	missense_variant	18/104	ENST00000680361.1	NP_001361665.1
DST	NM_001723.7 linkuse as main transcript	c.739C>G	p.Pro247Ala	missense_variant	4/24	ENST00000370765.11	NP_001714.1	Q03001-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000680361.1 linkuse as main transcript	c.2350C>G	p.Pro784Ala	missense_variant	18/104		NM_001374736.1	ENSP00000505098.1		A0A7P0T890
DST	ENST00000370765.11 linkuse as main transcript	c.739C>G	p.Pro247Ala	missense_variant	4/24	1	NM_001723.7	ENSP00000359801.6		Q03001-3

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

276

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000580

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00974

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00216

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00307

AC:

772

AN:

251424

Hom.:

AF XY:

0.00360

AC XY:

489

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00990

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00314

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00275

AC:

4022

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00296

AC XY:

2154

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.00295

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0102

Gnomad4 FIN exome

AF:

0.000412

Gnomad4 NFE exome

AF:

0.00244

Gnomad4 OTH exome

AF:

0.00328

GnomAD4 genome

AF:

0.00181

AC:

276

AN:

152256

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00975

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00216

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00228

Hom.:

Bravo

AF:

0.00188

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00330

AC:

400

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00245

EpiControl

AF:

0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DST: BP4, BS1, BS2 -

Hereditary sensory and autonomic neuropathy type 6

Uncertain:1Benign:1

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

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

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DST-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2019

This variant is classified as 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

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.010

.;.;.;.;T;.;T;.;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.84

T;T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0032

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;.;.;L;.;.;.;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.8

N;N;.;N;N;D;D;D;D

REVEL

Benign

0.033

Sift

Benign

0.052

T;D;.;T;D;D;T;D;T

Sift4G

Benign

0.43

.;.;.;.;.;T;T;T;T

Polyphen

0.023

B;.;.;.;.;B;.;B;B

Vest4

0.12

MVP

0.37

MPC

0.14

ClinPred

0.0017

GERP RS

1.6

gMVP

0.39

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