rs2842691

Variant names:

• chr6-7578590-G-A
• rs2842691
• NM_004415.4:c.3084+28G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-7578590-G-A
• chr6-7578590-G-C

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+28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.788 in 1,547,294 control chromosomes in the GnomAD database, including 481,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45585 hom., cov: 31)
  • Exomes 𝑓: 0.79 (435431 hom.)
• Consequence: DSP NM_004415.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.572
• Publications: 6 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):

• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• keratosis palmoplantaris striata 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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=-0.89).
• BP6: Variant 6-7578590-G-A is Benign according to our data. Variant chr6-7578590-G-A is described in ClinVar as Benign. ClinVar VariationId is 259384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.3084+28G>A		intron_variant	Intron 22 of 23	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.3084+28G>A		intron_variant	Intron 22 of 23		NP_001305963.1
DSP	NM_001008844.3	c.3084+28G>A		intron_variant	Intron 22 of 23		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.3084+28G>A		intron_variant	Intron 22 of 23	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes AF: 0.774 AC: 117198 AN: 151430 Hom.: 45551 Cov.: 31

Gnomad AFR AF: 0.730

Gnomad AMI AF: 0.864

Gnomad AMR AF: 0.805

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.798

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.834

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.798

GnomAD2 exomes AF: 0.781 AC: 194938 AN: 249528 AF XY: 0.782

Gnomad AFR exome AF: 0.730

Gnomad AMR exome AF: 0.789

Gnomad ASJ exome AF: 0.820

Gnomad EAS exome AF: 0.803

Gnomad FIN exome AF: 0.718

Gnomad NFE exome AF: 0.801

Gnomad OTH exome AF: 0.789

GnomAD4 exome AF: 0.789 AC: 1101582 AN: 1395748 Hom.: 435431 Cov.: 21 AF XY: 0.789 AC XY: 551001 AN XY: 698324

African (AFR) AF: 0.728 AC: 23303 AN: 32000

American (AMR) AF: 0.795 AC: 35296 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.818 AC: 20982 AN: 25666

East Asian (EAS) AF: 0.812 AC: 31907 AN: 39272

South Asian (SAS) AF: 0.747 AC: 63151 AN: 84496

European-Finnish (FIN) AF: 0.719 AC: 38136 AN: 53010

Middle Eastern (MID) AF: 0.806 AC: 4527 AN: 5620

European-Non Finnish (NFE) AF: 0.796 AC: 838326 AN: 1053180

Other (OTH) AF: 0.791 AC: 45954 AN: 58124

GnomAD4 genome AF: 0.774 AC: 117286 AN: 151546 Hom.: 45585 Cov.: 31 AF XY: 0.772 AC XY: 57155 AN XY: 74056

African (AFR) AF: 0.730 AC: 30179 AN: 41314

American (AMR) AF: 0.805 AC: 12245 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.827 AC: 2864 AN: 3462

East Asian (EAS) AF: 0.798 AC: 4109 AN: 5152

South Asian (SAS) AF: 0.749 AC: 3610 AN: 4818

European-Finnish (FIN) AF: 0.715 AC: 7483 AN: 10472

Middle Eastern (MID) AF: 0.842 AC: 246 AN: 292

European-Non Finnish (NFE) AF: 0.798 AC: 54096 AN: 67806

Other (OTH) AF: 0.794 AC: 1675 AN: 2110

Alfa AF: 0.782 Hom.: 8339

Bravo AF: 0.781

Asia WGS AF: 0.730 AC: 2532 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Woolly hair-skin fragility syndrome Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Keratosis palmoplantaris striata 2 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.34
PhyloP100		0.57
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: rs2842691; hg19: chr6-7578823;