rs137865390

Positions:

• chr6-56642705-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001723.7(DST):​c.84T>C​(p.Asn28=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: DST NM_001723.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.68

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 Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 6-56642705-A-G is Benign according to our data. Variant chr6-56642705-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 474556.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56642705-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.68 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001723.7	c.84T>C	p.Asn28=	synonymous_variant	1/24	ENST00000370765.11
DST	NM_001374736.1	c.1779-202T>C		intron_variant		ENST00000680361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000370765.11	c.84T>C	p.Asn28=	synonymous_variant	1/24	1	NM_001723.7
DST	ENST00000680361.1	c.1779-202T>C		intron_variant			NM_001374736.1

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000494 AC: 124 AN: 251144 Hom.: 0 AF XY: 0.000538 AC XY: 73 AN XY: 135714

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000987

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00109 AC: 1587 AN: 1461788 Hom.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 748 AN XY: 727190

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00136

Gnomad4 OTH exome AF: 0.000960

GnomAD4 genome AF: 0.000840 AC: 128 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74506

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000823 Hom.: 0

Bravo AF: 0.000691

EpiCase AF: 0.000982

EpiControl AF: 0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.71

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: rs137865390; hg19: chr6-56507503;