6-56620688-G-A

Position:

chr6-56620688-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000370765.11(DST):c.3346C>T(p.His1116Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,613,836 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1116R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.019 ( 94 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 100 hom. )

Consequence

DST
ENST00000370765.11 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.13

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=0.001804322).

BP6

Variant 6-56620688-G-A is Benign according to our data. Variant chr6-56620688-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 357588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56620688-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DST	NM_001723.7 linkuse as main transcript	c.3346C>T	p.His1116Tyr	missense_variant	23/24	ENST00000370765.11	NP_001714.1
DST	NM_001374736.1 linkuse as main transcript	c.4929+3842C>T		intron_variant		ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000370765.11 linkuse as main transcript	c.3346C>T	p.His1116Tyr	missense_variant	23/24	1	NM_001723.7	ENSP00000359801		Q03001-3
DST	ENST00000680361.1 linkuse as main transcript	c.4929+3842C>T		intron_variant			NM_001374736.1	ENSP00000505098

Frequencies

GnomAD3 genomes

AF:

0.0195

AC:

2961

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00754

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.00546

AC:

1368

AN:

250324

Hom.:

AF XY:

0.00383

AC XY:

519

AN XY:

135336

show subpopulations

Gnomad AFR exome

AF:

0.0691

Gnomad AMR exome

AF:

0.00582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00210

AC:

3063

AN:

1461600

Hom.:

100

Cov.:

AF XY:

0.00178

AC XY:

1293

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.0706

Gnomad4 AMR exome

AF:

0.00568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000854

Gnomad4 OTH exome

AF:

0.00523

GnomAD4 genome

AF:

0.0195

AC:

2964

AN:

152236

Hom.:

Cov.:

AF XY:

0.0186

AC XY:

1382

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0675

Gnomad4 AMR

AF:

0.00753

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00389

Hom.:

Bravo

AF:

0.0229

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0665

AC:

293

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00666

AC:

808

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
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

Jan 31, 2024

- -

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

-0.68

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

0.055

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

PROVEAN

Pathogenic

-5.0

REVEL

Benign

0.13

Sift

Benign

1.0

Sift4G

Uncertain

0.020

Polyphen

0.26

Vest4

0.29

MVP

0.30

ClinPred

0.027

GERP RS

4.4

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