rs78600049

chr6-56631291-G-Achr6-56631291-G-Cchr6-56631291-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001374736.1(DST):c.4062C>T(p.Val1354=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,613,884 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (36 hom.)
• Consequence: DST NM_001374736.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.50

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=-0.88).
• BP6: Variant 6-56631291-G-A is Benign according to our data. Variant chr6-56631291-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 357600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56631291-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0121 (1849/152188) while in subpopulation AFR AF= 0.0422 (1752/41512). AF 95% confidence interval is 0.0406. There are 30 homozygotes in gnomad4. There are 868 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001374736.1	c.4062C>T	p.Val1354=	synonymous_variant	30/104	ENST00000680361.1
DST	NM_001723.7	c.2451C>T	p.Val817=	synonymous_variant	16/24	ENST00000370765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000680361.1	c.4062C>T	p.Val1354=	synonymous_variant	30/104		NM_001374736.1
DST	ENST00000370765.11	c.2451C>T	p.Val817=	synonymous_variant	16/24	1	NM_001723.7

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1844 AN: 152070 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0422

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00479

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: 0.000118

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00354 AC: 891 AN: 251402 Hom.: 14 AF XY: 0.00250 AC XY: 340 AN XY: 135874

Gnomad AFR exome AF: 0.0443

Gnomad AMR exome AF: 0.00405

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: 0.000167

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00131 AC: 1916 AN: 1461696 Hom.: 36 Cov.: 31 AF XY: 0.00108 AC XY: 785 AN XY: 727154

Gnomad4 AFR exome AF: 0.0434

Gnomad4 AMR exome AF: 0.00389

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: 0.0000746

Gnomad4 OTH exome AF: 0.00315

GnomAD4 genome AF: 0.0121 AC: 1849 AN: 152188 Hom.: 30 Cov.: 32 AF XY: 0.0117 AC XY: 868 AN XY: 74404

Gnomad4 AFR AF: 0.0422

Gnomad4 AMR AF: 0.00478

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00381 Hom.: 5

Bravo AF: 0.0143

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

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	-0.88
Cadd	Benign	0.099
Dann	Benign	0.54

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: rs78600049; hg19: chr6-56496089;