6-7578586-T-G

Variant names:

• chr6-7578586-T-G
• rs2806229
• NM_004415.4:c.3084+24T>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.3084+24T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.784 in 1,576,868 control chromosomes in the GnomAD database, including 485,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43290 hom., cov: 31)
  • Exomes 𝑓: 0.79 (442428 hom.)
• Consequence: DSP NM_004415.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0270
• Publications: 8 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 (BayesDel_noAF=-0.84).
• BP6: Variant 6-7578586-T-G is Benign according to our data. Variant chr6-7578586-T-G is described in ClinVar as Benign. ClinVar VariationId is 259383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.792 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.3084+24T>G		intron	N/A	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.3084+24T>G		intron	N/A	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.3084+24T>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.3084+24T>G		intron	N/A	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.3084+24T>G		intron	N/A	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.2958+24T>G		intron	N/A	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.752 AC: 113963 AN: 151468 Hom.: 43271 Cov.: 31

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.863

Gnomad AMR AF: 0.797

Gnomad ASJ AF: 0.824

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.815

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.780

GnomAD2 exomes AF: 0.776 AC: 193921 AN: 249964 AF XY: 0.778

Gnomad AFR exome AF: 0.654

Gnomad AMR exome AF: 0.786

Gnomad ASJ exome AF: 0.817

Gnomad EAS exome AF: 0.803

Gnomad FIN exome AF: 0.720

Gnomad NFE exome AF: 0.801

Gnomad OTH exome AF: 0.785

GnomAD4 exome AF: 0.787 AC: 1121668 AN: 1425284 Hom.: 442428 Cov.: 23 AF XY: 0.787 AC XY: 559805 AN XY: 711420

African (AFR) AF: 0.644 AC: 20981 AN: 32566

American (AMR) AF: 0.791 AC: 35187 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.814 AC: 21064 AN: 25864

East Asian (EAS) AF: 0.813 AC: 32038 AN: 39420

South Asian (SAS) AF: 0.747 AC: 63672 AN: 85198

European-Finnish (FIN) AF: 0.720 AC: 38242 AN: 53086

Middle Eastern (MID) AF: 0.797 AC: 4539 AN: 5696

European-Non Finnish (NFE) AF: 0.796 AC: 859548 AN: 1079856

Other (OTH) AF: 0.785 AC: 46397 AN: 59120

GnomAD4 genome AF: 0.752 AC: 114033 AN: 151584 Hom.: 43290 Cov.: 31 AF XY: 0.751 AC XY: 55630 AN XY: 74082

African (AFR) AF: 0.656 AC: 27115 AN: 41322

American (AMR) AF: 0.797 AC: 12128 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 2855 AN: 3464

East Asian (EAS) AF: 0.797 AC: 4107 AN: 5154

South Asian (SAS) AF: 0.749 AC: 3611 AN: 4824

European-Finnish (FIN) AF: 0.715 AC: 7491 AN: 10480

Middle Eastern (MID) AF: 0.829 AC: 242 AN: 292

European-Non Finnish (NFE) AF: 0.797 AC: 54071 AN: 67818

Other (OTH) AF: 0.775 AC: 1633 AN: 2106

Alfa AF: 0.772 Hom.: 8509

Bravo AF: 0.756

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (1)
-	-	1	Keratosis palmoplantaris striata 2 (1)
-	-	1	Lethal acantholytic epidermolysis bullosa (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.2
DANN	Benign	0.50
PhyloP100		-0.027
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2806229; hg19: chr6-7578819; COSMIC: COSV65791251;