rs1060500615
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_004415.4(DSP):c.2933T>A(p.Ile978Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
DSP
NM_004415.4 missense
NM_004415.4 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 5.95
Genes affected
DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BP6
Variant 6-7577834-T-A is Benign according to our data. Variant chr6-7577834-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405241.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.2933T>A | p.Ile978Lys | missense_variant | Exon 21 of 24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.2933T>A | p.Ile978Lys | missense_variant | Exon 21 of 24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.2933T>A | p.Ile978Lys | missense_variant | Exon 21 of 24 | NP_001008844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.2933T>A | p.Ile978Lys | missense_variant | Exon 21 of 24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
DSP | ENST00000418664.2 | c.2933T>A | p.Ile978Lys | missense_variant | Exon 21 of 24 | 1 | ENSP00000396591.2 | |||
DSP | ENST00000710359.1 | c.2933T>A | p.Ile978Lys | missense_variant | Exon 21 of 24 | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
152212
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: 0.0000119 AC: 3AN: 251460Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135892
GnomAD3 exomes
AF:
AC:
3
AN:
251460
Hom.:
AF XY:
AC XY:
1
AN XY:
135892
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: 0.00000616 AC: 9AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727236
GnomAD4 exome
AF:
AC:
9
AN:
1461870
Hom.:
Cov.:
31
AF XY:
AC XY:
4
AN XY:
727236
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: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74362
GnomAD4 genome
AF:
AC:
1
AN:
152212
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74362
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:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Nov 10, 2016 | p.Ile978Lys (c.2933T>A) in the DSP gene (NM_004415.2) The lab classifies this variant as a variant of unknown significance. Given a lack of case data we consider this variant a variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been previously reported in the literature. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 0.942) and mutation taster predicts the variant to be disease causing (0.999). The lysine at codon 978 is conserved across close species, but the UCSC geneome browser reports the T at the position is not well conserved in other species suggesting there may be lack of conservation beyond the eight species reported in the mutation taster database. The nearest missense pathogenic or likely pathogenic entries into clinvar are at codons 895 987 and 1601. The variant resides at the end of the globular 1 domain of the desmoplakin domain which includes the first 1056 amino acids of the protein. Kapplinger et al., 2011 from Ackerman's group have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, 16% of 427 controls hosted missense variants-similar to the 21% yield in 175 Dutch and unit(s).S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC related genes need to be interpreted with cation. Kapplinger et al. Also report a "hot spot" for DSP variants between amino acids 250-604 in patients with ARVC but not in controls. In total the variant has not been seen in laboratory controls, published controls and individuals from publicly available population datasets. There are three individuals with p.Ile978Lys and two individuals with p.Ile978Val at codon 978 listed in the gnomAD dataset (http://gnomad.broadinstitute.org/). gnomAD currently includes variant calls on ~126,000 individuals of European, African, Latino and Asian descent (as of November 10, 2016). The average coverage at that site in gnomAD is around 50x. - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 19, 2023 | This missense variant replaces isoleucine with lysine at codon 978 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 3/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 21, 2023 | The p.I978K variant (also known as c.2933T>A), located in coding exon 21 of the DSP gene, results from a T to A substitution at nucleotide position 2933. The isoleucine at codon 978 is replaced by lysine, an amino acid with dissimilar properties. This variant co-occurred with an MYH7 variant in an individual from a dilated cardiomyopathy cohort (Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 19, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
DEOGEN2
Uncertain
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Loss of stability (P = 0.0101);Loss of stability (P = 0.0101);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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