6-7572029-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004415.4(DSP):c.2091A>G(p.Gly697Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,613,788 control chromosomes in the GnomAD database, including 475,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G697G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.78 ( 46213 hom., cov: 32)

Exomes 𝑓: 0.77 ( 428978 hom. )

Consequence

DSP
NM_004415.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:13

Conservation

PhyloP100: -0.844

Publications

23 publications found

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 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

DSP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 6-7572029-A-G is Benign according to our data. Variant chr6-7572029-A-G is described in ClinVar as Benign. ClinVar VariationId is 44870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.844 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) 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 link	c.2091A>G	p.Gly697Gly	synonymous_variant	Exon 15 of 24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.2091A>G	p.Gly697Gly	synonymous_variant	Exon 15 of 24		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.2091A>G	p.Gly697Gly	synonymous_variant	Exon 15 of 24		NP_001008844.1	P15924-2B4DKX6Q4LE79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 link	c.2091A>G	p.Gly697Gly	synonymous_variant	Exon 15 of 24	1	NM_004415.4	ENSP00000369129.3		P15924-1

Frequencies

GnomAD3 genomes

AF:

0.778

AC:

118340

AN:

152014

Hom.:

46193

Cov.:

show subpopulations

Gnomad AFR

AF:

0.800

Gnomad AMI

AF:

0.784

Gnomad AMR

AF:

0.789

Gnomad ASJ

AF:

0.844

Gnomad EAS

AF:

0.814

Gnomad SAS

AF:

0.688

Gnomad FIN

AF:

0.719

Gnomad MID

AF:

0.810

Gnomad NFE

AF:

0.773

Gnomad OTH

AF:

0.784

GnomAD2 exomes

AF:

0.763

AC:

191399

AN:

250974

AF XY:

0.758

show subpopulations

Gnomad AFR exome

AF:

0.802

Gnomad AMR exome

AF:

0.771

Gnomad ASJ exome

AF:

0.835

Gnomad EAS exome

AF:

0.807

Gnomad FIN exome

AF:

0.717

Gnomad NFE exome

AF:

0.771

Gnomad OTH exome

AF:

0.771

GnomAD4 exome

AF:

0.765

AC:

1118428

AN:

1461656

Hom.:

428978

Cov.:

AF XY:

0.764

AC XY:

555190

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.798

AC:

26728

AN:

33474

American (AMR)

AF:

0.775

AC:

34673

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.835

AC:

21830

AN:

26136

East Asian (EAS)

AF:

0.837

AC:

33218

AN:

39700

South Asian (SAS)

AF:

0.686

AC:

59134

AN:

86244

European-Finnish (FIN)

AF:

0.715

AC:

38169

AN:

53408

Middle Eastern (MID)

AF:

0.778

AC:

4487

AN:

5764

European-Non Finnish (NFE)

AF:

0.767

AC:

853330

AN:

1111830

Other (OTH)

AF:

0.776

AC:

46859

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

14423

28845

43268

57690

72113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20470

40940

61410

81880

102350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.778

AC:

118405

AN:

152132

Hom.:

46213

Cov.:

AF XY:

0.776

AC XY:

57701

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.799

AC:

33151

AN:

41494

American (AMR)

AF:

0.789

AC:

12071

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.844

AC:

2932

AN:

3472

East Asian (EAS)

AF:

0.813

AC:

4207

AN:

5172

South Asian (SAS)

AF:

0.689

AC:

3316

AN:

4816

European-Finnish (FIN)

AF:

0.719

AC:

7611

AN:

10582

Middle Eastern (MID)

AF:

0.810

AC:

238

AN:

294

European-Non Finnish (NFE)

AF:

0.773

AC:

52519

AN:

67980

Other (OTH)

AF:

0.781

AC:

1647

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1345

2690

4034

5379

6724

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

866

1732

2598

3464

4330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.775

Hom.:

34554

Bravo

AF:

0.789

Asia WGS

AF:

0.700

AC:

2434

AN:

3478

EpiCase

AF:

0.795

EpiControl

AF:

0.778

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 20, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 17, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 83.525% in gnomAD_ExomesFounderPop) based on the frequency threshold of 0.5% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.A synonymous variant not located in a splice region.1 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. -

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

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Mar 16, 2018

Color Diagnostics, LLC DBA Color Health

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

- -

Keratosis palmoplantaris striata 2

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 09, 2015

Ambry Genetics

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

-0.83

CADD

Benign

5.1

(source)

DANN

Benign

0.55

PhyloP100

-0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over