rs146263203

Positions:

• chr6-56618142-G-A
• chr6-56618142-G-C
• chr6-56618142-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001723.7(DST):​c.5892C>T​(p.Thr1964Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000947 in 1,614,032 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (1 hom.)
• Consequence: DST NM_001723.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.71

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 6-56618142-G-A is Benign according to our data. Variant chr6-56618142-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 357562.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr6-56618142-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.71 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DST	NM_001723.7	c.5892C>T	p.Thr1964Thr	synonymous_variant	23/24	ENST00000370765.11	NP_001714.1
DST	NM_001374736.1	c.4930-3658C>T		intron_variant		ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000370765.11	c.5892C>T	p.Thr1964Thr	synonymous_variant	23/24	1	NM_001723.7	ENSP00000359801.6
DST	ENST00000680361.1	c.4930-3658C>T		intron_variant			NM_001374736.1	ENSP00000505098.1

Frequencies

GnomAD3 genomes AF: 0.000737 AC: 112 AN: 152054 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000717 AC: 180 AN: 251124 Hom.: 0 AF XY: 0.000796 AC XY: 108 AN XY: 135706

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000952

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000969 AC: 1416 AN: 1461860 Hom.: 1 Cov.: 36 AF XY: 0.000954 AC XY: 694 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00107

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.000736 AC: 112 AN: 152172 Hom.: 1 Cov.: 32 AF XY: 0.000659 AC XY: 49 AN XY: 74386

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000579 Hom.: 0

Bravo AF: 0.000646

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	DST: BP4, BP7 -

Hereditary sensory and autonomic neuropathy type 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0070
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs146263203; hg19: chr6-56482940;