NM_004415.4:c.269A>G

Variant names:

• chr6-7555816-A-G
• rs188516326
• NM_004415.4:c.269A>G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 5.75

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 Benign. Variant got -9 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=8, Benign=2, Uncertain_significance=1}. 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].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000269 (41/152402) while in subpopulation EAS AF= 0.00674 (35/5190). AF 95% confidence interval is 0.00498. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.269A>G	p.Gln90Arg	missense_variant	Exon 2 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.269A>G	p.Gln90Arg	missense_variant	Exon 2 of 24		NP_001305963.1
DSP	NM_001008844.3	c.269A>G	p.Gln90Arg	missense_variant	Exon 2 of 24		NP_001008844.1
DSP	NM_001406591.1	c.269A>G	p.Gln90Arg	missense_variant	Exon 2 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.269A>G	p.Gln90Arg	missense_variant	Exon 2 of 24	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152284 Hom.: 0 Cov.: 33

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.: 1 AF XY: 0.000642 AC XY: 87 AN XY: 135486

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.: 1 Cov.: 32 AF XY: 0.000173 AC XY: 126 AN XY: 727016

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: 41 AN: 152402 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74536

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.: 1

Bravo AF: 0.000280

ExAC AF: 0.000634 AC: 77

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

Sep 21, 2015

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Dec 26, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiomyopathy Benign:2

Jul 02, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 16, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Oct 02, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Arrhythmogenic right ventricular dysplasia 8 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiovascular phenotype Benign:1

May 17, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 11, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	T
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.020	T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Uncertain	0.70	T
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	T
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

Other links and lift over

dbSNP: rs188516326; hg19: chr6-7556049;