chr6-7565478-C-G

Position:

• chr6-7565478-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_004415.4(DSP):​c.897C>G​(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 (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided 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 Likely_pathogenic. Variant got 7 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant 6-7565478-C-G is Pathogenic according to our data. Variant chr6-7565478-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 16838.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-7565478-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.897C>G	p.Ser299Arg	missense_variant	7/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.897C>G	p.Ser299Arg	missense_variant	7/24		NP_001305963.1
DSP	NM_001008844.3	c.897C>G	p.Ser299Arg	missense_variant	7/24		NP_001008844.1
DSP	NM_001406591.1	c.897C>G	p.Ser299Arg	missense_variant	7/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.897C>G	p.Ser299Arg	missense_variant	7/24	1	NM_004415.4	ENSP00000369129	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2002

- -

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	18
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.97	D;D
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
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

LitVar

Other links and lift over

dbSNP: rs121912992; hg19: chr6-7565711;