rs397516970

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004415.4(DSP):ā€‹c.8495G>Cā€‹(p.Gly2832Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2832V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

2
10
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.99
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DSPNM_004415.4 linkuse as main transcriptc.8495G>C p.Gly2832Ala missense_variant 24/24 ENST00000379802.8
DSPNM_001319034.2 linkuse as main transcriptc.7166G>C p.Gly2389Ala missense_variant 24/24
DSPNM_001008844.3 linkuse as main transcriptc.6698G>C p.Gly2233Ala missense_variant 24/24

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DSPENST00000379802.8 linkuse as main transcriptc.8495G>C p.Gly2832Ala missense_variant 24/241 NM_004415.4 P2P15924-1
DSPENST00000418664.2 linkuse as main transcriptc.6698G>C p.Gly2233Ala missense_variant 24/241 A2P15924-2
DSPENST00000710359.1 linkuse as main transcriptc.7166G>C p.Gly2389Ala missense_variant 24/24 A2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1456024
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
724152
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:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthApr 03, 2023This missense variant replaces glycine with alanine at codon 2832 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 not been reported in individuals affected with DSP-related disorders in the literature. This variant has not been identified 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
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 28, 2023This missense variant replaces glycine with alanine at codon 2832 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 not been reported in individuals affected with DSP-related disorders in the literature. This variant has not been identified 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.36
T;.
Eigen
Benign
0.044
Eigen_PC
Benign
-0.053
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.86
D;T
M_CAP
Benign
0.060
D
MetaRNN
Uncertain
0.74
D;D
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
2.0
M;.
MutationTaster
Benign
0.59
N;N
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-3.6
D;D
REVEL
Uncertain
0.36
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.99
D;.
Vest4
0.78
MutPred
0.22
Loss of glycosylation at S2831 (P = 0.0407);.;
MVP
0.82
MPC
0.85
ClinPred
0.99
D
GERP RS
3.5
Varity_R
0.29
gMVP
0.56

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: rs397516970; hg19: chr6-7585990; API