dbSNP rs41302885: DSP:p.Asp2070Asn (chr6-7583470-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004415.4(DSP):c.6208G>A(p.Asp2070Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,614,150 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2070H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0043 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 25 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:23

Conservation

PhyloP100: 8.15

Publications

16 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):

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

DSP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00889647).

BP6

Variant 6-7583470-G-A is Benign according to our data. Variant chr6-7583470-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44936.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00429 (654/152274) while in subpopulation AMR AF = 0.0133 (203/15306). AF 95% confidence interval is 0.0118. There are 4 homozygotes in GnomAd4. There are 325 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DSP	NM_004415.4	MANE Select	c.6208G>A	p.Asp2070Asn	missense	Exon 24 of 24	NP_004406.2	P15924-1
DSP	NM_001319034.2		c.4879G>A	p.Asp1627Asn	missense	Exon 24 of 24	NP_001305963.1	P15924-3
DSP	NM_001008844.3		c.4411G>A	p.Asp1471Asn	missense	Exon 24 of 24	NP_001008844.1	P15924-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DSP	ENST00000379802.8	TSL:1 MANE Select	c.6208G>A	p.Asp2070Asn	missense	Exon 24 of 24	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.3	TSL:1	c.4411G>A	p.Asp1471Asn	missense	Exon 24 of 24	ENSP00000396591.2	P15924-2
DSP	ENST00000713904.1		c.6082G>A	p.Asp2028Asn	missense	Exon 24 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes

AF:

0.00430

AC:

654

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00500

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.00410

AC:

1027

AN:

250724

AF XY:

0.00414

show subpopulations

Gnomad AFR exome

AF:

0.000372

Gnomad AMR exome

AF:

0.00512

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.00581

Gnomad OTH exome

AF:

0.00458

GnomAD4 exome

AF:

0.00424

AC:

6201

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

3143

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33480

American (AMR)

AF:

0.00447

AC:

200

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00800

AC:

209

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00121

AC:

104

AN:

86258

European-Finnish (FIN)

AF:

0.00257

AC:

137

AN:

53404

Middle Eastern (MID)

AF:

0.00832

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00469

AC:

5213

AN:

1112010

Other (OTH)

AF:

0.00435

AC:

263

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

449

897

1346

1794

2243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

186

372

558

744

930

<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:

0.00429

AC:

654

AN:

152274

Hom.:

Cov.:

AF XY:

0.00436

AC XY:

325

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41544

American (AMR)

AF:

0.0133

AC:

203

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00501

AC:

341

AN:

68020

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00468

Hom.:

Bravo

AF:

0.00449

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00390

AC:

474

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00687

EpiControl

AF:

0.00616

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

not specified (7)

Arrhythmogenic right ventricular dysplasia 8 (2)

Cardiomyopathy (2)

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)

Cardiovascular phenotype (1)

DSP-related disorder (1)

Lethal acantholytic epidermolysis bullosa (1)

Primary dilated cardiomyopathy (1)

Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0089

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.3

PhyloP100

8.1

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.35

Sift

Uncertain

0.0040

Sift4G

Benign

0.21

Polyphen

1.0

Vest4

0.58

MVP

0.78

MPC

0.81

ClinPred

0.020

GERP RS

5.1

Varity_R

0.42

gMVP

0.65

Mutation Taster

=85/15

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over