rs2842691

Positions:

• chr6-7578590-G-A
• chr6-7578590-G-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 259384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7578590-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
DSP	NM_004415.4	c.3084+28G>A		intron_variant		ENST00000379802.8
DSP	NM_001008844.3	c.3084+28G>A		intron_variant
DSP	NM_001319034.2	c.3084+28G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.3084+28G>A		intron_variant		1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3084+28G>A		intron_variant		1		A2
DSP	ENST00000710359.1	c.3084+28G>A		intron_variant				A2

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

GnomAD3 exomes AF: 0.781 AC: 194938 AN: 249528 Hom.: 76273 AF XY: 0.782 AC XY: 105435 AN XY: 134870

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 SAS exome AF: 0.743

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

Gnomad4 AFR exome AF: 0.728

Gnomad4 AMR exome AF: 0.795

Gnomad4 ASJ exome AF: 0.818

Gnomad4 EAS exome AF: 0.812

Gnomad4 SAS exome AF: 0.747

Gnomad4 FIN exome AF: 0.719

Gnomad4 NFE exome AF: 0.796

Gnomad4 OTH exome AF: 0.791

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

Gnomad4 AFR AF: 0.730

Gnomad4 AMR AF: 0.805

Gnomad4 ASJ AF: 0.827

Gnomad4 EAS AF: 0.798

Gnomad4 SAS AF: 0.749

Gnomad4 FIN AF: 0.715

Gnomad4 NFE AF: 0.798

Gnomad4 OTH AF: 0.794

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Woolly hair-skin fragility syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs2842691; hg19: chr6-7578823;