6-7582676-G-T

Variant names:

• chr6-7582676-G-T
• rs768161038
• NM_004415.4:c.5414G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004415.4(DSP):​c.5414G>T​(p.Cys1805Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.71

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20983854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.5414G>T	p.Cys1805Phe	missense_variant	Exon 24 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4085G>T	p.Cys1362Phe	missense_variant	Exon 24 of 24		NP_001305963.1
DSP	NM_001008844.3	c.3617G>T	p.Cys1206Phe	missense_variant	Exon 24 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.5414G>T	p.Cys1805Phe	missense_variant	Exon 24 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.3617G>T	p.Cys1206Phe	missense_variant	Exon 24 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.4085G>T	p.Cys1362Phe	missense_variant	Exon 24 of 24			ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461586 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine with phenylalanine at codon 1805 of the DSP protein (p.Cys1805Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with DSP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiomyopathy Uncertain:1

Feb 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces cysteine with phenylalanine at codon 1805 of the DSP protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with suspected arrhythmogenic right ventricular cardiomyopathy (PMID: 31470130) and in one individual affected with dilated cardiomyopathy (PMID: 37904629). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Dec 29, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Benign	0.76
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.0033
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.15
Sift	Benign	0.22	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.27	B;.
Vest4		0.46
MutPred		0.36		Gain of MoRF binding (P = 0.0681);.;
MVP		0.63
MPC		0.41
ClinPred		0.48	T
GERP RS		5.2
Varity_R		0.15
gMVP		0.19

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: rs768161038; hg19: chr6-7582909;