rs144275591

Positions:

• chr6-7585281-C-A
• chr6-7585281-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004415.4(DSP):​c.8019C>A​(p.Asp2673Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D2673D) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.870

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066903114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.8019C>A	p.Asp2673Glu	missense_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.6690C>A	p.Asp2230Glu	missense_variant	24/24		NP_001305963.1
DSP	NM_001008844.3	c.6222C>A	p.Asp2074Glu	missense_variant	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.8019C>A	p.Asp2673Glu	missense_variant	24/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.6222C>A	p.Asp2074Glu	missense_variant	24/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.6690C>A	p.Asp2230Glu	missense_variant	24/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74460

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.018
DANN	Benign	0.71
DEOGEN2	Benign	0.098	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.69	N;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.060
Sift	Benign	0.74	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.016	B;.
Vest4		0.14
MutPred		0.45		Gain of ubiquitination at K2668 (P = 0.1446);.;
MVP		0.41
MPC		0.21
ClinPred		0.14	T
GERP RS		-5.7
Varity_R		0.20
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-7585514;