6-7577860-T-C

Position:

• chr6-7577860-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_004415.4(DSP):​c.2959T>C​(p.Ser987Pro) variant causes a missense change. 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.85

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 6-7577860-T-C is Pathogenic according to our data. Variant chr6-7577860-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44888.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-7577860-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.2959T>C	p.Ser987Pro	missense_variant	21/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.2959T>C	p.Ser987Pro	missense_variant	21/24		NP_001305963.1
DSP	NM_001008844.3	c.2959T>C	p.Ser987Pro	missense_variant	21/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2959T>C	p.Ser987Pro	missense_variant	21/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.2959T>C	p.Ser987Pro	missense_variant	21/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.2959T>C	p.Ser987Pro	missense_variant	21/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 17, 2009

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;T
Polyphen		1.0	D;.
Vest4		0.89
MutPred		0.78		Gain of catalytic residue at S987 (P = 0.0646);Gain of catalytic residue at S987 (P = 0.0646);
MVP		0.98
MPC		0.92
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.81
gMVP		0.72

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: rs397516929; hg19: chr6-7578093;