rs2064217

Variant names:

• chr6-7577027-C-T
• rs2064217
• NM_004415.4:c.2862C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004415.4(DSP):​c.2862C>T​(p.Cys954Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,608,878 control chromosomes in the GnomAD database, including 47,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5792 hom., cov: 33)
  • Exomes 𝑓: 0.24 (41362 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.155
• Publications: 15 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):

• keratosis palmoplantaris striata 2

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen
• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 6-7577027-C-T is Benign according to our data. Variant chr6-7577027-C-T is described in ClinVar as Benign. ClinVar VariationId is 44886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.155 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004415.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	NM_004415.4	MANE Select	c.2862C>T	p.Cys954Cys	synonymous	Exon 20 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.2862C>T	p.Cys954Cys	synonymous	Exon 20 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.2862C>T	p.Cys954Cys	synonymous	Exon 20 of 24	NP_001008844.1	P15924-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000379802.8	TSL:1 MANE Select	c.2862C>T	p.Cys954Cys	synonymous	Exon 20 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.2862C>T	p.Cys954Cys	synonymous	Exon 20 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.2736C>T	p.Cys912Cys	synonymous	Exon 20 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40778 AN: 151880 Hom.: 5783 Cov.: 33

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.240 AC: 59673 AN: 249030 AF XY: 0.238

Gnomad AFR exome AF: 0.373

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.195

Gnomad FIN exome AF: 0.249

Gnomad NFE exome AF: 0.219

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.236 AC: 343133 AN: 1456880 Hom.: 41362 Cov.: 31 AF XY: 0.236 AC XY: 170722 AN XY: 724482

African (AFR) AF: 0.380 AC: 12670 AN: 33340

American (AMR) AF: 0.236 AC: 10477 AN: 44374

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5967 AN: 26040

East Asian (EAS) AF: 0.187 AC: 7392 AN: 39576

South Asian (SAS) AF: 0.265 AC: 22633 AN: 85542

European-Finnish (FIN) AF: 0.247 AC: 13161 AN: 53322

Middle Eastern (MID) AF: 0.237 AC: 1359 AN: 5740

European-Non Finnish (NFE) AF: 0.230 AC: 254979 AN: 1108752

Other (OTH) AF: 0.241 AC: 14495 AN: 60194

GnomAD4 genome AF: 0.269 AC: 40830 AN: 151998 Hom.: 5792 Cov.: 33 AF XY: 0.267 AC XY: 19829 AN XY: 74314

African (AFR) AF: 0.369 AC: 15296 AN: 41416

American (AMR) AF: 0.232 AC: 3550 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 784 AN: 3464

East Asian (EAS) AF: 0.202 AC: 1046 AN: 5176

South Asian (SAS) AF: 0.262 AC: 1261 AN: 4814

European-Finnish (FIN) AF: 0.247 AC: 2602 AN: 10542

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15457 AN: 67988

Other (OTH) AF: 0.264 AC: 558 AN: 2110

Alfa AF: 0.248 Hom.: 4554

Bravo AF: 0.271

Asia WGS AF: 0.281 AC: 979 AN: 3476

EpiCase AF: 0.215

EpiControl AF: 0.222

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Cardiomyopathy (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 8 (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Lethal acantholytic epidermolysis bullosa (1)
-	-	1	not provided (1)
-	-	1	Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	11
DANN	Benign	0.57
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs2064217; hg19: chr6-7577260; COSMIC: COSV65791881;