rs139350480

Positions:

chr6-56634196-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001374736.1(DST):c.3557G>A(p.Ser1186Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000985 in 1,613,668 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 8 hom. )

Consequence

DST
NM_001374736.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.91

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=0.0101264715).

BP6

Variant 6-56634196-C-T is Benign according to our data. Variant chr6-56634196-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56634196-C-T is described in Lovd as [Benign]. Variant chr6-56634196-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00525 (800/152288) while in subpopulation AFR AF= 0.0182 (756/41546). AF 95% confidence interval is 0.0171. There are 5 homozygotes in gnomad4. There are 377 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DST	NM_001374736.1 linkuse as main transcript	c.3557G>A	p.Ser1186Asn	missense_variant	27/104	ENST00000680361.1	NP_001361665.1
DST	NM_001723.7 linkuse as main transcript	c.1946G>A	p.Ser649Asn	missense_variant	13/24	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.3557G>A	p.Ser1186Asn	missense_variant	27/104		NM_001374736.1	ENSP00000505098.1		A0A7P0T890
DST	ENST00000370765.11 linkuse as main transcript	c.1946G>A	p.Ser649Asn	missense_variant	13/24	1	NM_001723.7	ENSP00000359801.6		Q03001-3

Frequencies

GnomAD3 genomes

AF:

0.00527

AC:

802

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00138

AC:

347

AN:

251086

Hom.:

AF XY:

0.00108

AC XY:

147

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.0186

Gnomad AMR exome

AF:

0.000954

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:

0.0000704

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000540

AC:

789

AN:

1461380

Hom.:

Cov.:

AF XY:

0.000442

AC XY:

321

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.0186

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.00525

AC:

800

AN:

152288

Hom.:

Cov.:

AF XY:

0.00506

AC XY:

377

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0182

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000871

Hom.:

Bravo

AF:

0.00634

ESP6500AA

AF:

0.0184

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00158

AC:

192

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2021	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

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 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

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

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

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

MetaRNN

Benign

0.010

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

MetaSVM

Uncertain

0.45

MutationAssessor

Pathogenic

3.0

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

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.6

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

REVEL

Uncertain

0.49

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0070

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

Polyphen

1.0

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

Vest4

0.68

MVP

0.83

MPC

0.55

ClinPred

0.035

GERP RS

5.0

gMVP

0.71

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