rs2076299

Variant names:

• chr6-7580725-A-G
• rs2076299
• NM_004415.4:c.4535A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004415.4(DSP):​c.4535A>G​(p.Tyr1512Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0735 in 1,613,944 control chromosomes in the GnomAD database, including 8,976 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1512F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (2425 hom., cov: 32)
  • Exomes 𝑓: 0.067 (6551 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:18
• Conservation: PhyloP100: 0.852
• Publications: 29 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002193749).
• BP6: Variant 6-7580725-A-G is Benign according to our data. Variant chr6-7580725-A-G is described in ClinVar as Benign. ClinVar VariationId is 44915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 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.4535A>G	p.Tyr1512Cys	missense	Exon 23 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.4050+485A>G		intron	N/A	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.3582+953A>G		intron	N/A	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.4535A>G	p.Tyr1512Cys	missense	Exon 23 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.3582+953A>G		intron	N/A	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.4409A>G	p.Tyr1470Cys	missense	Exon 23 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20929 AN: 152112 Hom.: 2415 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.0922

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0644

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0378

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.118 AC: 29557 AN: 249902 AF XY: 0.109

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.226

Gnomad ASJ exome AF: 0.0842

Gnomad EAS exome AF: 0.291

Gnomad FIN exome AF: 0.0635

Gnomad NFE exome AF: 0.0416

Gnomad OTH exome AF: 0.0842

GnomAD4 exome AF: 0.0667 AC: 97568 AN: 1461714 Hom.: 6551 Cov.: 33 AF XY: 0.0670 AC XY: 48746 AN XY: 727148

African (AFR) AF: 0.295 AC: 9867 AN: 33480

American (AMR) AF: 0.216 AC: 9644 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0867 AC: 2267 AN: 26136

East Asian (EAS) AF: 0.284 AC: 11291 AN: 39700

South Asian (SAS) AF: 0.135 AC: 11626 AN: 86258

European-Finnish (FIN) AF: 0.0643 AC: 3430 AN: 53312

Middle Eastern (MID) AF: 0.0867 AC: 500 AN: 5768

European-Non Finnish (NFE) AF: 0.0391 AC: 43482 AN: 1111946

Other (OTH) AF: 0.0904 AC: 5461 AN: 60390

GnomAD4 genome AF: 0.138 AC: 20977 AN: 152230 Hom.: 2425 Cov.: 32 AF XY: 0.141 AC XY: 10507 AN XY: 74426

African (AFR) AF: 0.289 AC: 11990 AN: 41516

American (AMR) AF: 0.193 AC: 2947 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0922 AC: 320 AN: 3470

East Asian (EAS) AF: 0.283 AC: 1462 AN: 5162

South Asian (SAS) AF: 0.141 AC: 679 AN: 4828

European-Finnish (FIN) AF: 0.0644 AC: 684 AN: 10622

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0378 AC: 2573 AN: 68022

Other (OTH) AF: 0.136 AC: 287 AN: 2116

Alfa AF: 0.0750 Hom.: 3449

Bravo AF: 0.152

TwinsUK AF: 0.0407 AC: 151

ALSPAC AF: 0.0394 AC: 152

ESP6500AA AF: 0.271 AC: 1193

ESP6500EA AF: 0.0442 AC: 380

ExAC AF: 0.115 AC: 13963

Asia WGS AF: 0.210 AC: 729 AN: 3478

EpiCase AF: 0.0397

EpiControl AF: 0.0393

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	1	2	not provided (3)
-	-	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	Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.85
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.10
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.45	P
Vest4		0.057
MPC		0.27
ClinPred		0.0080	T
GERP RS		1.8
Varity_R		0.046
gMVP		0.19
Mutation Taster		=84/16	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: rs2076299; hg19: chr6-7580958; COSMIC: COSV65792806;