rs751447598

Positions:

• chr6-7582960-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_004415.4(DSP):​c.5698G>A​(p.Glu1900Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.63

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 Likely_benign. Variant got -2 ACMG points.

• BP6: Variant 6-7582960-G-A is Benign according to our data. Variant chr6-7582960-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 578857.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.5698G>A	p.Glu1900Lys	missense_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4369G>A	p.Glu1457Lys	missense_variant	24/24		NP_001305963.1
DSP	NM_001008844.3	c.3901G>A	p.Glu1301Lys	missense_variant	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.5698G>A	p.Glu1900Lys	missense_variant	24/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.3901G>A	p.Glu1301Lys	missense_variant	24/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.4369G>A	p.Glu1457Lys	missense_variant	24/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251150 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0070	D;T
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.19		Gain of MoRF binding (P = 0.0579);.;
MVP		0.88
MPC		0.87
ClinPred		0.54	D
GERP RS		5.4
Varity_R		0.25
gMVP		0.46

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: rs751447598; hg19: chr6-7583193; COSMIC: COSV101131561;