rs121912999

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_004415.4(DSP):c.8501G>A(p.Arg2834His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,570 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2834C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 6.63

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]

DSP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-7585762-C-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

PP5

Variant 6-7585763-G-A is Pathogenic according to our data. Variant chr6-7585763-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16847.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr6-7585763-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.8501G>A	p.Arg2834His	missense_variant	Exon 24 of 24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.7172G>A	p.Arg2391His	missense_variant	Exon 24 of 24		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.6704G>A	p.Arg2235His	missense_variant	Exon 24 of 24		NP_001008844.1	P15924-2B4DKX6Q4LE79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSP	ENST00000379802.8 link	c.8501G>A	p.Arg2834His	missense_variant	Exon 24 of 24	1	NM_004415.4	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.2 link	c.6704G>A	p.Arg2235His	missense_variant	Exon 24 of 24	1		ENSP00000396591.2	P15924-2
DSP	ENST00000710359.1 link	c.7172G>A	p.Arg2391His	missense_variant	Exon 24 of 24			ENSP00000518230.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1455570

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723978

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:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:1

Mar 21, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg2834His variant in DSP has been reported in 1 individual with ARVC (Yang 2006). It was absent from large population studies. In vivo and in vitro functional studies, including a transgenic mouse model, demonstrate that the presence of this variant results in cardiomyocyte apoptosis, cardiac fibrosis, and cardiac dysfunction, which is consistent with ARVC (Yang 2006, Albrecht 2015, Martherus 2016). Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PS3, PM2, PP3. -

Arrhythmogenic right ventricular dysplasia 8

Pathogenic:1

Sep 15, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Uncertain:1

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2834 of the DSP protein (p.Arg2834His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 16917092). ClinVar contains an entry for this variant (Variation ID: 16847). 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. Experimental studies have shown that this missense change affects DSP function (PMID: 25733715, 26545710). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

D;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.2

L;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.3

D;D

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.88

MutPred

0.69

Loss of methylation at R2834 (P = 0.0279);.;

MVP

0.91

MPC

0.91

ClinPred

0.99

GERP RS

5.0

Varity_R

0.41

gMVP

0.59

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over