rs115542549

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001723.7(DST):c.6633A>G(p.Ala2211Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0384 in 1,614,152 control chromosomes in the GnomAD database, including 1,494 homozygotes. In-silico tool predicts 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 ( 1418 hom. )

Consequence

DST
NM_001723.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.712

Publications

7 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: Orphanet, Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

DST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 6-56616834-T-C is Benign according to our data. Variant chr6-56616834-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 357555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.712 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0249 (3787/152326) while in subpopulation NFE AF = 0.0417 (2834/68026). AF 95% confidence interval is 0.0404. There are 76 homozygotes in GnomAd4. There are 1679 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 76 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DST	NM_001723.7 link	c.6633A>G	p.Ala2211Ala	synonymous_variant	Exon 24 of 24	ENST00000370765.11	NP_001714.1	Q03001-3
DST	NM_001374736.1 link	c.4930-2350A>G		intron_variant	Intron 36 of 103	ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000370765.11 link	c.6633A>G	p.Ala2211Ala	synonymous_variant	Exon 24 of 24	1	NM_001723.7	ENSP00000359801.6		Q03001-3
DST	ENST00000680361.1 link	c.4930-2350A>G		intron_variant	Intron 36 of 103		NM_001374736.1	ENSP00000505098.1		A0A7P0T890

Frequencies

GnomAD3 genomes

AF:

0.0249

AC:

3785

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00798

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0139

Gnomad ASJ

AF:

0.0468

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0192

Gnomad FIN

AF:

0.00932

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0417

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0251

AC:

6297

AN:

251198

AF XY:

0.0258

show subpopulations

Gnomad AFR exome

AF:

0.00759

Gnomad AMR exome

AF:

0.0132

Gnomad ASJ exome

AF:

0.0469

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.0365

Gnomad OTH exome

AF:

0.0293

GnomAD4 exome

AF:

0.0398

AC:

58168

AN:

1461826

Hom.:

1418

Cov.:

AF XY:

0.0391

AC XY:

28435

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00636

AC:

213

AN:

33476

American (AMR)

AF:

0.0136

AC:

607

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0444

AC:

1160

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39696

South Asian (SAS)

AF:

0.0218

AC:

1884

AN:

86256

European-Finnish (FIN)

AF:

0.0133

AC:

710

AN:

53404

Middle Eastern (MID)

AF:

0.00485

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0462

AC:

51369

AN:

1111986

Other (OTH)

AF:

0.0363

AC:

2191

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

3363

6726

10088

13451

16814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2002

4004

6006

8008

10010

<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:

0.0249

AC:

3787

AN:

152326

Hom.:

Cov.:

AF XY:

0.0225

AC XY:

1679

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00796

AC:

331

AN:

41586

American (AMR)

AF:

0.0139

AC:

213

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0468

AC:

162

AN:

3464

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.0197

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00932

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0417

AC:

2834

AN:

68026

Other (OTH)

AF:

0.0237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

193

386

580

773

966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0342

Hom.:

Bravo

AF:

0.0244

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0374

EpiControl

AF:

0.0362

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

Mar 28, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary sensory and autonomic neuropathy type 6

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

0.71

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over