6-7585755-GGGATCTCGCTCC-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM4PP3BP6_Very_StrongBS1

The NM_004415.4(DSP):c.8508_8519delATCTCGCTCCGG(p.Ser2837_Gly2840del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,609,570 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

DSP
NM_004415.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 8.12

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_004415.4.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BP6

Variant 6-7585755-GGGATCTCGCTCC-G is Benign according to our data. Variant chr6-7585755-GGGATCTCGCTCC-G is described in ClinVar as [Likely_benign]. Clinvar id is 44975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000506 (77/152206) while in subpopulation AFR AF= 0.00132 (55/41524). AF 95% confidence interval is 0.00104. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.8508_8519delATCTCGCTCCGG	p.Ser2837_Gly2840del	disruptive_inframe_deletion	Exon 24 of 24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.7179_7190delATCTCGCTCCGG	p.Ser2394_Gly2397del	disruptive_inframe_deletion	Exon 24 of 24		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.6711_6722delATCTCGCTCCGG	p.Ser2238_Gly2241del	disruptive_inframe_deletion	Exon 24 of 24		NP_001008844.1	P15924-2B4DKX6Q4LE79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSP	ENST00000379802.8 link	c.8508_8519delATCTCGCTCCGG	p.Ser2837_Gly2840del	disruptive_inframe_deletion	Exon 24 of 24	1	NM_004415.4	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.2 link	c.6711_6722delATCTCGCTCCGG	p.Ser2238_Gly2241del	disruptive_inframe_deletion	Exon 24 of 24	1		ENSP00000396591.2	P15924-2
DSP	ENST00000710359.1 link	c.7179_7190delATCTCGCTCCGG	p.Ser2394_Gly2397del	disruptive_inframe_deletion	Exon 24 of 24			ENSP00000518230.1

Frequencies

GnomAD3 genomes

AF:

0.000500

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000243

AC:

AN:

246768

Hom.:

AF XY:

0.000262

AC XY:

AN XY:

133792

show subpopulations

Gnomad AFR exome

AF:

0.00119

Gnomad AMR exome

AF:

0.0000889

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000233

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000251

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000169

AC:

247

AN:

1457364

Hom.:

AF XY:

0.000155

AC XY:

112

AN XY:

724800

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.0000909

Gnomad4 ASJ exome

AF:

0.0000772

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000175

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000145

Gnomad4 OTH exome

AF:

0.000233

GnomAD4 genome

AF:

0.000506

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00132

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000552

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 17, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DSP c.8508_8519delATCTCGCTCCGG (p.Ser2843_Arg2846del) results in an in-frame deletion in a repeat region that is predicted to remove 4 amino acids from the encoded protein. The variant allele was found at a frequency of 0.00024 in 246768 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002). c.8508_8519delATCTCGCTCCGG has been reported in the literature in at least 1 individual affected with decreased left ventricular ejection fraction (example, Carrick_2024). It was also observed in at least 1 healthy control individual (example, Kapplinger_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 39011630, 36437915, 36212137, 25445213, 21636032). ClinVar contains an entry for this variant (Variation ID: 44975). Based on the evidence outlined above, the variant was classified as benign. -

Feb 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser2843_Arg2846del in exon 24 of DSP: This variant is not expected to have cli nical significance because it has been identified in 0.4% (50/11494) of Latino c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org). This in-frame deletion of four amino acids occurs within a region of repe ating amino acids. It can result from several different DNA deletions, and is pr esent in mammals (dolphin, opossum, and platypus) and other evolutionarily dista nt species. -

Cardiomyopathy

Benign:2

Mar 04, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Benign:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Jul 17, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27532257, 24503780, 21636032, 25445213, 31402444) -

Cardiovascular phenotype

Benign:1

Sep 07, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over