rs958098310

chr6-7583849-C-T

Variant summary

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

The NM_004415.4(DSP):c.6587C>T(p.Thr2196Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,136 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T2196A) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.97

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]

ACMG classification

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
DSP	NM_004415.4	c.6587C>T	p.Thr2196Ile	missense_variant	24/24	ENST00000379802.8
DSP	NM_001319034.2	c.5258C>T	p.Thr1753Ile	missense_variant	24/24
DSP	NM_001008844.3	c.4790C>T	p.Thr1597Ile	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.6587C>T	p.Thr2196Ile	missense_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.4790C>T	p.Thr1597Ile	missense_variant	24/24	1		A2
DSP	ENST00000710359.1	c.5258C>T	p.Thr1753Ile	missense_variant	24/24			A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 07, 2023

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. ClinVar contains an entry for this variant (Variation ID: 575874). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 29606362). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2196 of the DSP protein (p.Thr2196Ile). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2020

The p.T2196I variant (also known as c.6587C>T), located in coding exon 24 of the DSP gene, results from a C to T substitution at nucleotide position 6587. The threonine at codon 2196 is replaced by isoleucine, an amino acid with similar properties. This variant was reported in one individual from an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort (Ruiz Salas A et al. Rev Esp Cardiol (Engl Ed), 2018 Dec;71:1018-1026). This amino acid position is well conserved in available 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	0.96	D;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.97	D;.
Vest4		0.77
MutPred		0.47		Gain of catalytic residue at L2201 (P = 0.0713);.;
MVP		0.70
MPC		0.85
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.53
gMVP		0.85

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

Other links and lift over

dbSNP: rs958098310; hg19: chr6-7584082;