rs150191284

Positions:

• chr6-56615702-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.16

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]

ACMG classification

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	c.7765A>G	p.Ile2589Val	missense_variant	24/24	ENST00000370765.11
DST	NM_001374736.1	c.4930-1218A>G		intron_variant		ENST00000680361.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3786 AN: 152240 Hom.: 75 Cov.: 32

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

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.: 34 AF XY: 0.0391 AC XY: 28416 AN XY: 727166

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.: 76 Cov.: 32 AF XY: 0.0226 AC XY: 1681 AN XY: 74512

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: 35

ESP6500EA AF: 0.0427 AC: 367

ExAC AF: 0.0239 AC: 2902

Asia WGS AF: 0.0190 AC: 65 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

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	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.98
Eigen	Benign	-0.048
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.83	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.18
Sift	Benign	0.20	T
Sift4G	Benign	0.66	T
Polyphen		0.015	B
Vest4		0.036
ClinPred		0.0092	T
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

Other links and lift over

dbSNP: rs150191284; hg19: chr6-56480500;