rs2230863

chr6-56619054-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001723.7(DST):c.4980A>C(p.Val1660=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00674 in 1,614,152 control chromosomes in the GnomAD database, including 467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (212 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (255 hom.)
• Consequence: DST NM_001723.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.35

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-56619054-T-G is Benign according to our data. Variant chr6-56619054-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 357569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56619054-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0999 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001723.7	c.4980A>C	p.Val1660=	synonymous_variant	23/24	ENST00000370765.11
DST	NM_001374736.1	c.4930-4570A>C		intron_variant		ENST00000680361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000370765.11	c.4980A>C	p.Val1660=	synonymous_variant	23/24	1	NM_001723.7
DST	ENST00000680361.1	c.4930-4570A>C		intron_variant			NM_001374736.1

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4675 AN: 152210 Hom.: 210 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0196

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.0224

GnomAD3 exomes AF: 0.0105 AC: 2635 AN: 250924 Hom.: 90 AF XY: 0.00841 AC XY: 1141 AN XY: 135608

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.00892

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0231

Gnomad SAS exome AF: 0.000785

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.000697

Gnomad OTH exome AF: 0.00867

GnomAD4 exome AF: 0.00423 AC: 6190 AN: 1461824 Hom.: 255 Cov.: 36 AF XY: 0.00377 AC XY: 2744 AN XY: 727204

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.00979

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.0155

Gnomad4 SAS exome AF: 0.000823

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.000433

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.0308 AC: 4693 AN: 152328 Hom.: 212 Cov.: 32 AF XY: 0.0299 AC XY: 2230 AN XY: 74490

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0199

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.000764

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0152 Hom.: 61

Bravo AF: 0.0358

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 12, 2021

- -

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_noAF	Benign	-0.72
Cadd	Benign	0.088
Dann	Benign	0.69

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: rs2230863; hg19: chr6-56483852; COSMIC: COSV55023412;