rs75671065

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001723.7(DST):c.25C>T(p.Arg9Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,614,004 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 16 hom. )

Consequence

DST
NM_001723.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.23

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008616298).

BP6

Variant 6-56642764-G-A is Benign according to our data. Variant chr6-56642764-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 357622.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=2}. Variant chr6-56642764-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001723.7 linkuse as main transcript	c.25C>T	p.Arg9Cys	missense_variant	1/24	ENST00000370765.11
DST	NM_001374736.1 linkuse as main transcript	c.1779-261C>T		intron_variant		ENST00000680361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000370765.11 linkuse as main transcript	c.25C>T	p.Arg9Cys	missense_variant	1/24	1	NM_001723.7		Q03001-3
DST	ENST00000680361.1 linkuse as main transcript	c.1779-261C>T		intron_variant			NM_001374736.1

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

326

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0102

Gnomad FIN

AF:

0.0111

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00343

AC:

858

AN:

249942

Hom.:

AF XY:

0.00389

AC XY:

525

AN XY:

135098

show subpopulations

Gnomad AFR exome

AF:

0.000556

Gnomad AMR exome

AF:

0.000897

Gnomad ASJ exome

AF:

0.00608

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00967

Gnomad FIN exome

AF:

0.0111

Gnomad NFE exome

AF:

0.00179

Gnomad OTH exome

AF:

0.00328

GnomAD4 exome

AF:

0.00234

AC:

3416

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

1827

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.00628

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00989

Gnomad4 FIN exome

AF:

0.0118

Gnomad4 NFE exome

AF:

0.00142

Gnomad4 OTH exome

AF:

0.00232

GnomAD4 genome

AF:

0.00215

AC:

327

AN:

152252

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

200

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0104

Gnomad4 FIN

AF:

0.0111

Gnomad4 NFE

AF:

0.00165

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00193

Hom.:

Bravo

AF:

0.00107

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00351

AC:

426

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DST: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2022	See Variant Classification Assertion Criteria. -

Hereditary sensory and autonomic neuropathy type 6

Uncertain:1

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

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

.;.;.;T

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

D;D;D;D

MetaRNN

Benign

0.0086

T;T;T;T

MetaSVM

Benign

-0.57

PROVEAN

Benign

-1.9

N;N;N;D

REVEL

Benign

0.13

Sift

Uncertain

0.0060

D;D;D;D

Sift4G

Uncertain

0.018

.;D;D;D

Polyphen

0.69

P;D;P;P

Vest4

0.19

MVP

0.36

MPC

0.55

ClinPred

0.065

GERP RS

5.0

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