rs79026338

Positions:

• chr6-56634464-G-A

Variant summary

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

The NM_001374736.1(DST):​c.3492C>T​(p.Asn1164=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0021 in 1,614,070 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: DST NM_001374736.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.8814
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.45

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 (BayesDel_noAF=-0.53).
• BP6: Variant 6-56634464-G-A is Benign according to our data. Variant chr6-56634464-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 357606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56634464-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1660/152232) while in subpopulation AFR AF= 0.0379 (1572/41532). AF 95% confidence interval is 0.0363. There are 25 homozygotes in gnomad4. There are 778 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001374736.1	c.3492C>T	p.Asn1164=	splice_region_variant, synonymous_variant	26/104	ENST00000680361.1
DST	NM_001723.7	c.1881C>T	p.Asn627=	splice_region_variant, synonymous_variant	12/24	ENST00000370765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000680361.1	c.3492C>T	p.Asn1164=	splice_region_variant, synonymous_variant	26/104		NM_001374736.1
DST	ENST00000370765.11	c.1881C>T	p.Asn627=	splice_region_variant, synonymous_variant	12/24	1	NM_001723.7

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1659 AN: 152114 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0379

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00315 AC: 793 AN: 251408 Hom.: 11 AF XY: 0.00222 AC XY: 301 AN XY: 135872

Gnomad AFR exome AF: 0.0388

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00119 AC: 1737 AN: 1461838 Hom.: 34 Cov.: 32 AF XY: 0.000975 AC XY: 709 AN XY: 727206

Gnomad4 AFR exome AF: 0.0390

Gnomad4 AMR exome AF: 0.00376

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000656

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.0109 AC: 1660 AN: 152232 Hom.: 25 Cov.: 32 AF XY: 0.0105 AC XY: 778 AN XY: 74424

Gnomad4 AFR AF: 0.0379

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00472 Hom.: 6

Bravo AF: 0.0128

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

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 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 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	-0.53
CADD	Benign	13
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		0.010		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: rs79026338; hg19: chr6-56499262;