chr6-56615702-T-C

Position:

chr6-56615702-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001723.7(DST):c.7765A>G(p.Ile2589Val) variant causes a missense change. The variant allele was found at a frequency of 0.0384 in 1,614,094 control chromosomes in the GnomAD database, including 1,495 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 76 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1419 hom. )

Consequence

DST
NM_001723.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.16

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066128075).

BP6

Variant 6-56615702-T-C is Benign according to our data. Variant chr6-56615702-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 357543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56615702-T-C is described in Lovd as [Benign]. Variant chr6-56615702-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0249 (3788/152358) while in subpopulation NFE AF= 0.0416 (2833/68026). AF 95% confidence interval is 0.0404. There are 76 homozygotes in gnomad4. There are 1681 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 76 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001723.7 linkuse as main transcript	c.7765A>G	p.Ile2589Val	missense_variant	24/24	ENST00000370765.11
DST	NM_001374736.1 linkuse as main transcript	c.4930-1218A>G		intron_variant		ENST00000680361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000370765.11 linkuse as main transcript	c.7765A>G	p.Ile2589Val	missense_variant	24/24	1	NM_001723.7		Q03001-3
DST	ENST00000680361.1 linkuse as main transcript	c.4930-1218A>G		intron_variant			NM_001374736.1

Frequencies

GnomAD3 genomes

AF:

0.0249

AC:

3786

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00803

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0139

Gnomad ASJ

AF:

0.0464

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.0192

Gnomad FIN

AF:

0.00941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0416

Gnomad OTH

AF:

0.0244

GnomAD3 exomes

AF:

0.0251

AC:

6302

AN:

251224

Hom.:

114

AF XY:

0.0259

AC XY:

3511

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00751

Gnomad AMR exome

AF:

0.0132

Gnomad ASJ exome

AF:

0.0470

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0217

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.0365

Gnomad OTH exome

AF:

0.0294

GnomAD4 exome

AF:

0.0398

AC:

58117

AN:

1461736

Hom.:

1419

Cov.:

AF XY:

0.0391

AC XY:

28416

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00639

Gnomad4 AMR exome

AF:

0.0136

Gnomad4 ASJ exome

AF:

0.0444

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0219

Gnomad4 FIN exome

AF:

0.0133

Gnomad4 NFE exome

AF:

0.0462

Gnomad4 OTH exome

AF:

0.0363

GnomAD4 genome

AF:

0.0249

AC:

3788

AN:

152358

Hom.:

Cov.:

AF XY:

0.0226

AC XY:

1681

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00801

Gnomad4 AMR

AF:

0.0139

Gnomad4 ASJ

AF:

0.0464

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0197

Gnomad4 FIN

AF:

0.00941

Gnomad4 NFE

AF:

0.0416

Gnomad4 OTH

AF:

0.0241

Alfa

AF:

0.0363

Hom.:

172

Bravo

AF:

0.0244

TwinsUK

AF:

0.0445

AC:

165

ALSPAC

AF:

0.0506

AC:

195

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.0427

AC:

367

ExAC

AF:

0.0239

AC:

2902

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0374

EpiControl

AF:

0.0362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

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

-0.52

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.048

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0066

MetaSVM

Benign

-0.83

PROVEAN

Benign

0.070

REVEL

Benign

0.18

Sift

Benign

0.20

Sift4G

Benign

0.66

Polyphen

0.015

Vest4

0.036

ClinPred

0.0092

GERP RS

4.5

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