rs2076300

Variant names:

• chr6-7584384-C-T
• rs2076300
• NM_004415.4:c.7122C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-7584384-C-T
• chr6-7584384-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004415.4(DSP):​c.7122C>T​(p.Thr2374Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 1,613,850 control chromosomes in the GnomAD database, including 89,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6708 hom., cov: 31)
  • Exomes 𝑓: 0.33 (82550 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: -5.08
• Publications: 27 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-7584384-C-T is Benign according to our data. Variant chr6-7584384-C-T is described in ClinVar as Benign. ClinVar VariationId is 44947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.351 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.7122C>T	p.Thr2374Thr	synonymous	Exon 24 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.5793C>T	p.Thr1931Thr	synonymous	Exon 24 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.5325C>T	p.Thr1775Thr	synonymous	Exon 24 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.7122C>T	p.Thr2374Thr	synonymous	Exon 24 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.5325C>T	p.Thr1775Thr	synonymous	Exon 24 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.6996C>T	p.Thr2332Thr	synonymous	Exon 24 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42856 AN: 151926 Hom.: 6703 Cov.: 31

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.0811

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.288

GnomAD2 exomes AF: 0.288 AC: 72500 AN: 251380 AF XY: 0.297

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.0651

Gnomad FIN exome AF: 0.331

Gnomad NFE exome AF: 0.356

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.330 AC: 482087 AN: 1461806 Hom.: 82550 Cov.: 61 AF XY: 0.330 AC XY: 240104 AN XY: 727200

African (AFR) AF: 0.163 AC: 5454 AN: 33476

American (AMR) AF: 0.206 AC: 9209 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 11348 AN: 26136

East Asian (EAS) AF: 0.0902 AC: 3581 AN: 39698

South Asian (SAS) AF: 0.265 AC: 22824 AN: 86254

European-Finnish (FIN) AF: 0.327 AC: 17467 AN: 53414

Middle Eastern (MID) AF: 0.397 AC: 2292 AN: 5768

European-Non Finnish (NFE) AF: 0.351 AC: 390834 AN: 1111950

Other (OTH) AF: 0.316 AC: 19078 AN: 60396

GnomAD4 genome AF: 0.282 AC: 42867 AN: 152044 Hom.: 6708 Cov.: 31 AF XY: 0.280 AC XY: 20779 AN XY: 74320

African (AFR) AF: 0.168 AC: 6959 AN: 41440

American (AMR) AF: 0.263 AC: 4020 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1512 AN: 3468

East Asian (EAS) AF: 0.0811 AC: 420 AN: 5178

South Asian (SAS) AF: 0.250 AC: 1202 AN: 4810

European-Finnish (FIN) AF: 0.338 AC: 3571 AN: 10574

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24096 AN: 67964

Other (OTH) AF: 0.285 AC: 603 AN: 2114

Alfa AF: 0.331 Hom.: 36226

Bravo AF: 0.273

Asia WGS AF: 0.152 AC: 531 AN: 3478

EpiCase AF: 0.378

EpiControl AF: 0.372

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.12
DANN	Benign	0.65
PhyloP100		-5.1
Mutation Taster		=79/21	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: rs2076300; hg19: chr6-7584617; COSMIC: COSV65791917;