NM_004415.4:c.2684A>G

Variant names:

• chr6-7576347-A-G
• rs367752002
• NM_004415.4:c.2684A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_004415.4(DSP):​c.2684A>G​(p.Tyr895Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y895H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:9 B:3
• Conservation: PhyloP100: 5.43
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• keratosis palmoplantaris striata 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• striate palmoplantar keratoderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe dermatitis-multiple allergies-metabolic wasting syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000107 (157/1461814) while in subpopulation MID AF = 0.00191 (11/5766). AF 95% confidence interval is 0.00107. There are 0 homozygotes in GnomAdExome4. There are 87 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.2684A>G	p.Tyr895Cys	missense_variant	Exon 19 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.2684A>G	p.Tyr895Cys	missense_variant	Exon 19 of 24		NP_001305963.1
DSP	NM_001008844.3	c.2684A>G	p.Tyr895Cys	missense_variant	Exon 19 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2684A>G	p.Tyr895Cys	missense_variant	Exon 19 of 24	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000171 AC: 43 AN: 251304 AF XY: 0.000199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000107 AC: 157 AN: 1461814 Hom.: 0 Cov.: 34 AF XY: 0.000120 AC XY: 87 AN XY: 727210

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86256

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53412

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5766

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1111974

Other (OTH) AF: 0.000182 AC: 11 AN: 60394

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000927 Hom.: 1

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:9 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 15, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#163257; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26112015, 31110529)

Jun 23, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr895Cys variant in DSP has been seen in 2 individuals with Arrhythmogenic right ventricular cardiomyopathy (Caforio 2020 PMID: 32114801, LMM data). It has also been identified in 0.08% (6/7212) of Other and 0.059% (18/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 163257). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, BS1.

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

May 17, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr895Cys variant (rs367752002) has not been reported in the medical literature nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 163257). It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.0004% (identified in 41 out of 277,050 chromosomes). The tyrosine at codon 895 is moderately conserved considering 12 species (Alamut software v2.9), and computational analyses return mixed results regarding the effect of this variant on DSP protein structure/function (SIFT: tolerated, PolyPhen2: possibly damaging, and Mutation Taster: disease causing). Thus, based on the available information, the clinical significance of the p.Tyr895Cys variant cannot be determined with certainty.

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces tyrosine with cysteine at codon 895 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 been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 32114801) and in an individual affected with hypertrophic cardiomyopathy (PMID: 31110529). This variant has also been identified in 44/282708 chromosomes 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.

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Sep 18, 2014

Blueprint Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cardiomyopathy Uncertain:1

May 14, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces tyrosine with cysteine at codon 895 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 been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 32114801) and in an individual affected with hypertrophic cardiomyopathy (PMID: 31110529). This variant has also been identified in 44/282708 chromosomes 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.

Primary dilated cardiomyopathy Uncertain:1

Genetics and Genomics Program, Sidra Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Uncertain:1

Oct 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Nov 18, 2024

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.2684A>G (p.Tyr895Cys) results in a non-conservative amino acid change located in the Spectrin/alpha-actinin repeats region (IPR018159) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 1607178 control chromosomes, predominantly at a frequency of 0.00055 within the South Asian subpopulation in the gnomAD database (v4.1 dataset). The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.75 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002). c.2684A>G has been reported in the literature in heterozygous state in at least one individual affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) and in an individual affected with dilated cardiomyopathy (DCM), and was also found in two siblings affected with eosinophilic esophagitis (EoE) (e.g. Caforio_2020, Al-Shafai_2021, Shoda_2021). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. At least one publication reported experimental evidence evaluating the role of this variant in EoE, and found decreased barrier integrity, altered signaling, and increased degradation compared to wild type in human esophageal cell lines (Shoda_2021); authors proposed an association with EoE based on their findings, however they also noted that although these findings might be related to EoE, they are likely distinct from other phenotypes such as arrhythmias. The following publications have been ascertained in the context of this evaluation (PMID: 34815391, 32114801, 34137518). ClinVar contains an entry for this variant (Variation ID: 163257). Based on the evidence outlined above, the variant was classified as likely benign.

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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Jun 08, 2022

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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		5.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.21
Sift	Benign	0.087	T;T
Sift4G	Benign	0.095	T;T
Vest4		0.88
ClinPred		0.12	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.58
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs367752002; hg19: chr6-7576580;