rs188516326

Positions:

chr6-7555816-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_004415.4(DSP):c.269A>G(p.Gln90Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000188 in 1,613,836 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 5.75

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:

DSP (HGNC:):

DSP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020286888).

BP6

Variant 6-7555816-A-G is Benign according to our data. Variant chr6-7555816-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163236.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1, Benign=2}. Variant chr6-7555816-A-G is described in Lovd as [Pathogenic]. Variant chr6-7555816-A-G is described in Lovd as [Benign]. Variant chr6-7555816-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4 linkuse as main transcript	c.269A>G	p.Gln90Arg	missense_variant	2/24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 linkuse as main transcript	c.269A>G	p.Gln90Arg	missense_variant	2/24		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 linkuse as main transcript	c.269A>G	p.Gln90Arg	missense_variant	2/24		NP_001008844.1	P15924-2B4DKX6Q4LE79
DSP	NM_001406591.1 linkuse as main transcript	c.269A>G	p.Gln90Arg	missense_variant	2/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.269A>G	p.Gln90Arg	missense_variant	2/24	1	NM_004415.4	ENSP00000369129.3		P15924-1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152284

Hom.:

Cov.:

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:

0.00654

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000710

AC:

178

AN:

250556

Hom.:

AF XY:

0.000642

AC XY:

AN XY:

135486

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00926

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000180

AC:

263

AN:

1461434

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

126

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00522

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.000269

AC:

AN:

152402

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74536

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00674

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000367

Hom.:

Bravo

AF:

0.000280

ExAC

AF:

0.000634

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 21, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the weak case data, presence in controls, and presence of a more convincing variant in one of the reported cases, we consider this variant to be a variant of uncertain significance, probably benign. The variant has been seen in at least 2 unrelated cases of ARVC). Yang et al (2006) reported the variant in 1 of 66 individuals in the North American ARVD registry. The same group later reported a patient with this variant and a frameshift in PKP2 (Xu et al 2010). Presumably these are the same patient, though insufficient data is reported to assess that. A British group observed the variant in 1 of 149 ARVC probands in their cohort (Cox et al 2011). Ancestry data was not provided in either report. In silico analysis with PolyPhen-2 predicts the variant to be benign. In total the variant has been seen in 5 of 6972 published controls and individuals from publicly available population datasets. The variant is present in 5 of 544 alleles (likely 5/272 individuals) from Asian individuals in the 1000 genomes sample. There is no variation at codon 90 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of May 16th, 2014). The variant was not observed in the following laboratory and published control samples: 200 individuals (Yang et al 2006). -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 18, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.Gln90Arg vari ant in DSP has been identified in 0.9% (75/8002) of East Asian chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs18 8516326). At this frequency a disease causing role is highly unlikely. However, published data appears to favor a role in disease although there is some concer n regarding the validity of the claims made by the authors. This variant has bee n reported in at least 1 individual with ARVC who carried a frameshift variant i n PKP2 that would be expected to contribute to disease (Yang 2006, Xu 2010, Cox 2011 - note that there is some suspicion that the same individual was reported b y all 3 studies). One of these studies claimed de novo occurrence of the p.Gln90 Arg variant (without providing information on verification of paternity) and dis qualified the (more convincing) PKP2 variant based on its presence in two unaffe cted relatives (Xu 2010). In vitro functional studies showed that this variant may impact protein function (Yang 2006), though this type of assay may not accur ately represent biological function. In summary, the frequency of the p.Gln90Arg variant strongly suggests that it is more likely to be benign; however, due to the strongly conflicting published data additional information is needed to ful ly assess its clinical significance. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 26, 2018	Variant summary: DSP c.269A>G (p.Gln90Arg) results in a conservative amino acid change located in the JUP/PKP binding domain (Yang_2006) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0. 0.00072 in 281004control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.0092 including 1 homozygote (gnomAD and publication data). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 46-fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.269A>G, has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and sudden death but also in controls (Yang_2006, Zhang_2016, Cox_2011). Co-occurrences with other pathogenic variant(s) have been reported (c.1211dupT (p.Val406fsX4)), providing supporting evidence for a benign role (Xu_2010, Cox_2011). One publication reports experimental evidence showing that the variant protein was mainly detected in the cytoplasm and did not accumulate at cell membranes (or cell junctions), with two transgenic founder mice showing severely reduced ventricular wall thickness (Yang_2006). Another study showed that this variant does not affect the binding of the iASPP protein (Notari_2015). The clinical significance of these in-vitro and in-vivo studies is not clear. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS x3, likely benign x1, benign x1). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 02, 2018	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Lethal acantholytic epidermolysis bullosa

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Woolly hair-skin fragility syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2020

This variant is associated with the following publications: (PMID: 21606396, 32466575, 22995991, 25691752, 25616645, 21606390, 26585738, 25856671, 26332594, 20152563, 16917092, 30897878, 31402444) -

Arrhythmogenic right ventricular dysplasia 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DSP-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.078

MetaRNN

Benign

0.020

T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.69

N;N

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.7

N;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;T

Polyphen

0.97

D;.

Vest4

0.90

MVP

0.94

MPC

0.83

ClinPred

0.13

GERP RS

5.9

Varity_R

0.32

gMVP

0.74

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