dbSNP rs115983672: DST:p.Thr2134Met (chr6-56617066-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001723.7(DST):c.6401C>T(p.Thr2134Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,976 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T2134T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

DST
NM_001723.7 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:5

Conservation

PhyloP100: 2.54

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

hereditary sensory and autonomic neuropathy type 6
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet

DST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010834843).

BP6

Variant 6-56617066-G-A is Benign according to our data. Variant chr6-56617066-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 474540.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0011 (168/152256) while in subpopulation AMR AF = 0.00307 (47/15296). AF 95% confidence interval is 0.00237. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001723.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DST	NM_001723.7	MANE Plus Clinical	c.6401C>T	p.Thr2134Met	missense	Exon 24 of 24	NP_001714.1	Q03001-3
DST	NM_001374736.1	MANE Select	c.4930-2582C>T		intron	N/A	NP_001361665.1	A0A7P0T890
DST	NM_001374734.1		c.4957-2582C>T		intron	N/A	NP_001361663.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.6401C>T	p.Thr2134Met	missense	Exon 24 of 24	ENSP00000359801.6	Q03001-3
DST	ENST00000680361.1	MANE Select	c.4930-2582C>T		intron	N/A	ENSP00000505098.1	A0A7P0T890
DST	ENST00000244364.10	TSL:1	c.3319-2582C>T		intron	N/A	ENSP00000244364.6	Q03001-8

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

169

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00147

AC:

369

AN:

250844

AF XY:

0.00165

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.00167

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00113

AC:

1648

AN:

1461720

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

850

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33472

American (AMR)

AF:

0.00107

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00336

AC:

290

AN:

86234

European-Finnish (FIN)

AF:

0.000861

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00106

AC:

1180

AN:

1111920

Other (OTH)

AF:

0.000977

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

190

284

379

474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00110

AC:

168

AN:

152256

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41536

American (AMR)

AF:

0.00307

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00140

AC:

AN:

68006

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00138

Hom.:

Bravo

AF:

0.00116

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00158

AC:

192

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.00148

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

DST-related disorder (1)

Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.14

Eigen_PC

Benign

0.0083

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.68

M_CAP

Benign

0.0065

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.1

PhyloP100

2.5

PROVEAN

Benign

-0.49

REVEL

Benign

0.040

Sift

Benign

0.094

Sift4G

Uncertain

0.0020

Polyphen

0.13

Vest4

0.16

MVP

0.36

ClinPred

0.0028

GERP RS

4.8

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over