rs369682599

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_004415.4(DSP):​c.8482G>A​(p.Gly2828Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000745 in 1,610,202 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 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

1
10
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 6.25
Variant links:
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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DSPNM_004415.4 linkc.8482G>A p.Gly2828Ser missense_variant Exon 24 of 24 ENST00000379802.8 NP_004406.2 P15924-1B4DKX6
DSPNM_001319034.2 linkc.7153G>A p.Gly2385Ser missense_variant Exon 24 of 24 NP_001305963.1 P15924-3B4DKX6
DSPNM_001008844.3 linkc.6685G>A p.Gly2229Ser missense_variant Exon 24 of 24 NP_001008844.1 P15924-2B4DKX6Q4LE79

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkc.8482G>A p.Gly2828Ser missense_variant Exon 24 of 24 1 NM_004415.4 ENSP00000369129.3 P15924-1
DSPENST00000418664.2 linkc.6685G>A p.Gly2229Ser missense_variant Exon 24 of 24 1 ENSP00000396591.2 P15924-2
DSPENST00000710359.1 linkc.7153G>A p.Gly2385Ser missense_variant Exon 24 of 24 ENSP00000518230.1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152096
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000364
AC:
9
AN:
247242
Hom.:
0
AF XY:
0.0000224
AC XY:
3
AN XY:
134128
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000294
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000993
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000358
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.0000768
AC:
112
AN:
1458106
Hom.:
0
Cov.:
33
AF XY:
0.0000841
AC XY:
61
AN XY:
725058
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000679
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000466
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000928
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152096
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000100
Hom.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 01, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: DSP c.8482G>A (p.Gly2828Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 247242 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8482G>A in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 405239). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Nov 30, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces glycine with serine at codon 2828 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 an individual affected with idiopathic ventricular fibrillation (PMID: 31114860). This variant has been identified in 14/278596 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. -

Cardiomyopathy Uncertain:1
Jul 15, 2024
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces glycine with serine at codon 2828 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 an individual affected with idiopathic ventricular fibrillation (PMID: 31114860), and in another individual who experienced sudden infant death (PMID: 37589201). This variant has been identified in 14/278596 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
Nov 05, 2018
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.G2828S variant (also known as c.8482G>A), located in coding exon 24 of the DSP gene, results from a G to A substitution at nucleotide position 8482. The glycine at codon 2828 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, serine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Uncertain:1
Dec 15, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Jul 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.11
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Benign
0.072
D
MetaRNN
Uncertain
0.57
D;D
MetaSVM
Benign
-0.38
T
MutationAssessor
Benign
1.5
L;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-3.1
D;D
REVEL
Uncertain
0.35
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.012
D;D
Polyphen
1.0
D;.
Vest4
0.55
MVP
0.70
MPC
0.82
ClinPred
0.80
D
GERP RS
4.5
Varity_R
0.61
gMVP
0.48

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs369682599; hg19: chr6-7585977; API