6-56639590-G-A

Position:

chr6-56639590-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001374736.1(DST):c.2719C>T(p.Arg907Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,613,438 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

DST
NM_001374736.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.84

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DST	NM_001374736.1 linkuse as main transcript	c.2719C>T	p.Arg907Trp	missense_variant	21/104	ENST00000680361.1	NP_001361665.1
DST	NM_001723.7 linkuse as main transcript	c.1108C>T	p.Arg370Trp	missense_variant	7/24	ENST00000370765.11	NP_001714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000680361.1 linkuse as main transcript	c.2719C>T	p.Arg907Trp	missense_variant	21/104		NM_001374736.1	ENSP00000505098
DST	ENST00000370765.11 linkuse as main transcript	c.1108C>T	p.Arg370Trp	missense_variant	7/24	1	NM_001723.7	ENSP00000359801		Q03001-3

Frequencies

GnomAD3 genomes

AF:

0.0000922

AC:

AN:

151822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251110

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461616

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000922

AC:

AN:

151822

Hom.:

Cov.:

AF XY:

0.0000810

AC XY:

AN XY:

74108

show subpopulations

Gnomad4 AFR

AF:

0.000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000966

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 370 of the DST protein (p.Arg370Trp). This variant is present in population databases (rs775464446, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DST-related conditions. ClinVar contains an entry for this variant (Variation ID: 357611). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2020

The p.R874W variant (also known as c.2620C>T), located in coding exon 20 of the DST gene, results from a C to T substitution at nucleotide position 2620. The arginine at codon 874 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary sensory and autonomic neuropathy type 6

Uncertain:1

Uncertain significance, 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

-0.015

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

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

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Benign

0.75

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.64

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.3

.;.;.;M;.;.;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-6.4

D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.44

MVP

0.74

MPC

0.49

ClinPred

0.65

GERP RS

3.4

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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