rs777852039

Variant names:

• chr6-7566392-C-G
• rs777852039
• NM_004415.4:c.955C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-7566392-C-G
• chr6-7566392-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_004415.4(DSP):​c.955C>G​(p.Leu319Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L319L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.448

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 4 ACMG points.

• PM1: In a repeat Spectrin 2 (size 103) in uniprot entity DESP_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_004415.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.955C>G	p.Leu319Val	missense_variant	Exon 8 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.955C>G	p.Leu319Val	missense_variant	Exon 8 of 24		NP_001305963.1
DSP	NM_001008844.3	c.955C>G	p.Leu319Val	missense_variant	Exon 8 of 24		NP_001008844.1
DSP	NM_001406591.1	c.955C>G	p.Leu319Val	missense_variant	Exon 8 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.955C>G	p.Leu319Val	missense_variant	Exon 8 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.955C>G	p.Leu319Val	missense_variant	Exon 8 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.955C>G	p.Leu319Val	missense_variant	Exon 8 of 24			ENSP00000518230.1
DSP	ENST00000682228.1	n.279C>G		non_coding_transcript_exon_variant	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Sep 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with valine at codon 319 of the DSP protein (p.Leu319Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. 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. ClinVar contains an entry for this variant (Variation ID: 405252). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	D;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;T
Polyphen		0.99	D;.
Vest4		0.69
MutPred		0.27		Loss of catalytic residue at L319 (P = 0.0542);Loss of catalytic residue at L319 (P = 0.0542);
MVP		0.85
MPC		0.82
ClinPred		0.98	D
GERP RS		2.6
Varity_R		0.64
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777852039; hg19: chr6-7566625;