6-56628047-A-C

Position:

chr6-56628047-A-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.4590T>G(p.Asn1530Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,613,758 control chromosomes in the GnomAD database, including 224 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 109 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 115 hom. )

Consequence

DST
NM_001374736.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.78

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=0.001757592).

BP6

Variant 6-56628047-A-C is Benign according to our data. Variant chr6-56628047-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 357595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56628047-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0744 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.4590T>G	p.Asn1530Lys	missense_variant	33/104	ENST00000680361.1	NP_001361665.1
DST	NM_001723.7 linkuse as main transcript	c.2979T>G	p.Asn993Lys	missense_variant	19/24	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.4590T>G	p.Asn1530Lys	missense_variant	33/104		NM_001374736.1	ENSP00000505098.1		A0A7P0T890
DST	ENST00000370765.11 linkuse as main transcript	c.2979T>G	p.Asn993Lys	missense_variant	19/24	1	NM_001723.7	ENSP00000359801.6		Q03001-3

Frequencies

GnomAD3 genomes

AF:

0.0220

AC:

3351

AN:

151976

Hom.:

106

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0763

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00859

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.00616

AC:

1548

AN:

251370

Hom.:

AF XY:

0.00458

AC XY:

622

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.0826

Gnomad AMR exome

AF:

0.00385

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00254

AC:

3716

AN:

1461664

Hom.:

115

Cov.:

AF XY:

0.00225

AC XY:

1637

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.0796

Gnomad4 AMR exome

AF:

0.00487

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000460

Gnomad4 OTH exome

AF:

0.00492

GnomAD4 genome

AF:

0.0222

AC:

3373

AN:

152094

Hom.:

109

Cov.:

AF XY:

0.0221

AC XY:

1644

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0766

Gnomad4 AMR

AF:

0.00858

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.00300

Hom.:

Bravo

AF:

0.0253

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0781

AC:

344

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00708

AC:

860

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2021	- -

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

Jan 31, 2024

- -

DST-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 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). -

Hereditary sensory and autonomic neuropathy type 6

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.067

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

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.63

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.83

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

MetaRNN

Benign

0.0018

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.4

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

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.1

D;D;.;D;D;D;D;D;D

REVEL

Benign

0.083

Sift

Benign

0.15

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

Sift4G

Benign

0.40

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

Polyphen

0.0020

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

Vest4

0.32

MVP

0.30

MPC

0.18

ClinPred

0.045

GERP RS

-1.3

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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