rs121912992

Variant names:

• chr6-7565478-C-A
• NM_004415.4:c.897C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-7565478-C-A
• chr6-7565478-C-G
• chr6-7565478-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PP3_Moderate PP5_Moderate

The NM_004415.4(DSP):​c.897C>A​(p.Ser299Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.454

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 Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_004415.4 (DSP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 6-7565478-C-A is Pathogenic according to our data. Variant chr6-7565478-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2954090.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.897C>A	p.Ser299Arg	missense_variant	Exon 7 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.897C>A	p.Ser299Arg	missense_variant	Exon 7 of 24		NP_001305963.1
DSP	NM_001008844.3	c.897C>A	p.Ser299Arg	missense_variant	Exon 7 of 24		NP_001008844.1
DSP	NM_001406591.1	c.897C>A	p.Ser299Arg	missense_variant	Exon 7 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.897C>A	p.Ser299Arg	missense_variant	Exon 7 of 24	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 299 of the DSP protein (p.Ser299Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 12373648). It has also been observed to segregate with disease in related individuals. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.045	D;T
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.81		Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);
MVP		0.99
MPC		0.87
ClinPred		0.99	D
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.90

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: chr6-7565711;