rs115983672

chr6-56617066-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001723.7(DST):c.6401C>T(p.Thr2134Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,976 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T2134T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: DST NM_001723.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 2.54

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 (MetaRNN=0.010834843).
• BP6: Variant 6-56617066-G-A is Benign according to our data. Variant chr6-56617066-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474540.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-56617066-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001723.7	c.6401C>T	p.Thr2134Met	missense_variant	24/24	ENST00000370765.11
DST	NM_001374736.1	c.4930-2582C>T		intron_variant		ENST00000680361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000370765.11	c.6401C>T	p.Thr2134Met	missense_variant	24/24	1	NM_001723.7
DST	ENST00000680361.1	c.4930-2582C>T		intron_variant			NM_001374736.1

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00147 AC: 369 AN: 250844 Hom.: 1 AF XY: 0.00165 AC XY: 224 AN XY: 135564

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00363

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00113 AC: 1648 AN: 1461720 Hom.: 2 Cov.: 34 AF XY: 0.00117 AC XY: 850 AN XY: 727132

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00336

Gnomad4 FIN exome AF: 0.000861

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74462

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00116

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00158 AC: 192

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00148

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

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	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	18
Dann	Uncertain	0.98
Eigen	Benign	-0.14
Eigen_PC	Benign	0.0083
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.040
Sift	Benign	0.094	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.13	B
Vest4		0.16
MVP		0.36
ClinPred		0.0028	T
GERP RS		4.8

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: rs115983672; hg19: chr6-56481864; COSMIC: COSV55045539; COSMIC: COSV55045539;