6-7585798-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004415.4(DSP):​c.8536C>T​(p.Arg2846Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2846G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

8
10
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.25
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DSPNM_004415.4 linkc.8536C>T p.Arg2846Trp missense_variant Exon 24 of 24 ENST00000379802.8 NP_004406.2 P15924-1B4DKX6
DSPNM_001319034.2 linkc.7207C>T p.Arg2403Trp missense_variant Exon 24 of 24 NP_001305963.1 P15924-3B4DKX6
DSPNM_001008844.3 linkc.6739C>T p.Arg2247Trp 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.8536C>T p.Arg2846Trp missense_variant Exon 24 of 24 1 NM_004415.4 ENSP00000369129.3 P15924-1
DSPENST00000418664.2 linkc.6739C>T p.Arg2247Trp missense_variant Exon 24 of 24 1 ENSP00000396591.2 P15924-2
DSPENST00000710359.1 linkc.7207C>T p.Arg2403Trp missense_variant Exon 24 of 24 ENSP00000518230.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1458618
Hom.:
0
Cov.:
33
AF XY:
0.00000276
AC XY:
2
AN XY:
725592
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Apr 05, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. 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. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2846 of the DSP protein (p.Arg2846Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSP-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.73
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
D;.
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.80
D;D
MetaSVM
Uncertain
-0.28
T
MutationAssessor
Uncertain
2.3
M;.
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-4.1
D;D
REVEL
Uncertain
0.50
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;.
Vest4
0.71
MutPred
0.28
Loss of methylation at R2846 (P = 0.0391);.;
MVP
0.75
MPC
0.83
ClinPred
1.0
D
GERP RS
2.9
Varity_R
0.44
gMVP
0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-7586031; COSMIC: COSV60939203; COSMIC: COSV60939203; API