rs200421954
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_004415.4(DSP):āc.4775A>Gā(p.Lys1592Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000271 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00016 ( 0 hom., cov: 32)
Exomes š: 0.00028 ( 0 hom. )
Consequence
DSP
NM_004415.4 missense
NM_004415.4 missense
Scores
2
2
15
Clinical Significance
Conservation
PhyloP100: 6.10
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BP6
Variant 6-7580965-A-G is Benign according to our data. Variant chr6-7580965-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188466.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=3, Uncertain_significance=4}. Variant chr6-7580965-A-G is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.4775A>G | p.Lys1592Arg | missense_variant | 23/24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.4050+725A>G | intron_variant | NP_001305963.1 | ||||
DSP | NM_001008844.3 | c.3582+1193A>G | intron_variant | NP_001008844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.4775A>G | p.Lys1592Arg | missense_variant | 23/24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
DSP | ENST00000418664.2 | c.3582+1193A>G | intron_variant | 1 | ENSP00000396591.2 | |||||
DSP | ENST00000710359.1 | c.4050+725A>G | intron_variant | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 152216Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000232 AC: 58AN: 250148Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135566
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GnomAD4 exome AF: 0.000283 AC: 413AN: 1461782Hom.: 0 Cov.: 32 AF XY: 0.000275 AC XY: 200AN XY: 727182
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GnomAD4 genome AF: 0.000158 AC: 24AN: 152334Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74494
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | DSP: PM2, BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 07, 2022 | Reported in association with HCM, ARVC, and sudden unexplained death (Cox et al., 2011; Bagnall et al., 2014; Bhonsale et al., 2015; Lopes et al., 2015); Reported in a male with sudden cardiac arrest at 28 years old, unrelated to exercise; this individual had no clear cardiac phenotype and also harbored a novel splice site variant in the TTN gene (Asatryan et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25351510, 24440382, 25616645, 21606396, 27153395, 30975432) - |
Cardiomyopathy Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 16, 2023 | This missense variant replaces lysine with arginine at codon 1592 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606396), in an individual with sudden death (PMID: 24440382), and in a sudden cardiac arrest survivor (PMID: 30975432). This variant occurs at an elevated allele frequency in the general population and has been identified in 65/281550 chromosomes 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. - |
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 29, 2022 | - - |
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 23, 2024 | This missense variant replaces lysine with arginine at codon 1592 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606396), in an individual with sudden death (PMID: 24440382), and in a sudden cardiac arrest survivor (PMID: 30975432). This variant occurs at an elevated allele frequency in the general population and has been identified in 65/281550 chromosomes 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 24, 2022 | Variant summary: DSP c.4775A>G (p.Lys1592Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 250148 control chromosomes, predominantly at a frequency of 0.00041 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 41 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.4775A>G has been reported in the literature in one individual affected with ARVD, one individual with a history of syncope and one individual with sudden cardiac arrest (Cox_2011, Bagnall_2014, Asatryan_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia/Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. At-least one co-occurrence with another pathogenic variant has been observed in an individual undergoing evaluation on a Familial Arrhythmia Panel at our laboratory ( KCNQ1 c.1124_1127delTTCA, p.Ile375fs, Long QT syndrome), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Benign
M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at