rs146392434
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001723.7(DST):āc.6023T>Cā(p.Leu2008Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000079 ( 0 hom., cov: 32)
Exomes š: 0.000010 ( 0 hom. )
Consequence
DST
NM_001723.7 missense
NM_001723.7 missense
Scores
6
8
Clinical Significance
Conservation
PhyloP100: 5.69
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DST | NM_001723.7 | c.6023T>C | p.Leu2008Pro | missense_variant | 23/24 | ENST00000370765.11 | |
DST | NM_001374736.1 | c.4930-3527T>C | intron_variant | ENST00000680361.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DST | ENST00000370765.11 | c.6023T>C | p.Leu2008Pro | missense_variant | 23/24 | 1 | NM_001723.7 | ||
DST | ENST00000680361.1 | c.4930-3527T>C | intron_variant | NM_001374736.1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152192Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
12
AN:
152192
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251338Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135838
GnomAD3 exomes
AF:
AC:
8
AN:
251338
Hom.:
AF XY:
AC XY:
5
AN XY:
135838
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461826Hom.: 0 Cov.: 36 AF XY: 0.00000963 AC XY: 7AN XY: 727216
GnomAD4 exome
AF:
AC:
15
AN:
1461826
Hom.:
Cov.:
36
AF XY:
AC XY:
7
AN XY:
727216
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74346
GnomAD4 genome
?
AF:
AC:
12
AN:
152192
Hom.:
Cov.:
32
AF XY:
AC XY:
8
AN XY:
74346
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
2
ESP6500EA
AF:
AC:
0
ExAC
?
AF:
AC:
6
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2008 of the DST protein (p.Leu2008Pro). This variant is present in population databases (rs146392434, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DST-related conditions. ClinVar contains an entry for this variant (Variation ID: 541455). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Uncertain
D
MetaSVM
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
ClinPred
T
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at