6-7562999-T-G

Variant names:

• chr6-7562999-T-G
• rs2076295
• NM_004415.4:c.726+219T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004415.4(DSP):​c.726+219T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 152,042 control chromosomes in the GnomAD database, including 15,880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.45 (15880 hom., cov: 32)
• Consequence: DSP NM_004415.4 intron
• Clinical Significance: Benign criteria provided, single submitter P:1 U:1 B:1 O:2
• Conservation: PhyloP100: -0.0580
• Publications: 91 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-7562999-T-G is Benign according to our data. Variant chr6-7562999-T-G is described in ClinVar as Benign. ClinVar VariationId is 672128.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.507 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.726+219T>G		intron	N/A	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.726+219T>G		intron	N/A	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.726+219T>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.726+219T>G		intron	N/A	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.726+219T>G		intron	N/A	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.600+219T>G		intron	N/A	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68786 AN: 151924 Hom.: 15842 Cov.: 32

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.445

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.453 AC: 68868 AN: 152042 Hom.: 15880 Cov.: 32 AF XY: 0.443 AC XY: 32896 AN XY: 74338

African (AFR) AF: 0.513 AC: 21258 AN: 41454

American (AMR) AF: 0.403 AC: 6161 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1440 AN: 3472

East Asian (EAS) AF: 0.467 AC: 2414 AN: 5168

South Asian (SAS) AF: 0.330 AC: 1593 AN: 4826

European-Finnish (FIN) AF: 0.366 AC: 3862 AN: 10562

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30780 AN: 67954

Other (OTH) AF: 0.441 AC: 933 AN: 2116

Alfa AF: 0.455 Hom.: 47899

Bravo AF: 0.465

Asia WGS AF: 0.385 AC: 1341 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Chronic obstructive pulmonary disease (1)
-	-	1	not provided (1)
-	-	-	Combined pulmonary fibrosis-emphysema syndrome (1)
-	-	-	Interstitial lung disease 2 (1)
-	-	-	Susceptibility to severe coronavirus disease (COVID-19) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.9
DANN	Benign	0.71
PhyloP100		-0.058
Mutation Taster		=98/2	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: rs2076295; hg19: chr6-7563232; COSMIC: COSV65791349;