6-7585729-C-G

Variant names:

• chr6-7585729-C-G
• rs142717240
• NM_004415.4:c.8467C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_004415.4(DSP):​c.8467C>G​(p.Pro2823Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000523 in 1,612,342 control chromosomes in the GnomAD database, including 3 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. P2823L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (3 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:8
• Conservation: PhyloP100: 5.54
• Publications: 5 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):

• 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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14003846).
• BP6: Variant 6-7585729-C-G is Benign according to our data. Variant chr6-7585729-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44969.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000553 (808/1460032) while in subpopulation NFE AF = 0.00064 (711/1110968). AF 95% confidence interval is 0.0006. There are 3 homozygotes in GnomAdExome4. There are 404 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	NM_004415.4	MANE Select	c.8467C>G	p.Pro2823Ala	missense	Exon 24 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.7138C>G	p.Pro2380Ala	missense	Exon 24 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.6670C>G	p.Pro2224Ala	missense	Exon 24 of 24	NP_001008844.1	P15924-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000379802.8	TSL:1 MANE Select	c.8467C>G	p.Pro2823Ala	missense	Exon 24 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.6670C>G	p.Pro2224Ala	missense	Exon 24 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.8341C>G	p.Pro2781Ala	missense	Exon 24 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000322 AC: 80 AN: 248538 AF XY: 0.000319

Gnomad AFR exome AF: 0.000191

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000553

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000553 AC: 808 AN: 1460032 Hom.: 3 Cov.: 38 AF XY: 0.000556 AC XY: 404 AN XY: 726170

African (AFR) AF: 0.000150 AC: 5 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000569 AC: 49 AN: 86102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.000640 AC: 711 AN: 1110968

Other (OTH) AF: 0.000697 AC: 42 AN: 60294

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74474

African (AFR) AF: 0.0000481 AC: 2 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000454 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	1	Arrhythmogenic right ventricular dysplasia 8 (2)
-	-	2	Cardiomyopathy (2)
-	-	2	not specified (2)
-	-	1	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Lethal acantholytic epidermolysis bullosa (1)
-	1	-	Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.28
MVP		0.59
MPC		0.81
ClinPred		0.15	T
GERP RS		5.0
Varity_R		0.34
gMVP		0.45
Mutation Taster		=65/35	polymorphism

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: rs142717240; hg19: chr6-7585962;