rs1554109062

Positions:

• chr6-7584950-T-TGAAAAA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_004415.4(DSP):​c.7689_7694dup​(p.Lys2564_Asn2565insLysLys) variant causes a inframe insertion 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004415.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.7689_7694dup	p.Lys2564_Asn2565insLysLys	inframe_insertion	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3	c.5892_5897dup	p.Lys1965_Asn1966insLysLys	inframe_insertion	24/24		NP_001008844.1
DSP	NM_001319034.2	c.6360_6365dup	p.Lys2121_Asn2122insLysLys	inframe_insertion	24/24		NP_001305963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.7689_7694dup	p.Lys2564_Asn2565insLysLys	inframe_insertion	24/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.5892_5897dup	p.Lys1965_Asn1966insLysLys	inframe_insertion	24/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.6360_6365dup	p.Lys2121_Asn2122insLysLys	inframe_insertion	24/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 12, 2016

In summary, this is a rare in-frame 2-codon gain with unknown impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DSP-related disease. This sequence change inserts 6 nucleotides in exon 24 of the DSP mRNA (c.7689_7694dupGAAAAA). This leads to the insertion of 2 amino acid residue(s) in the DSP protein (p.Lys2564_Asn2565insLysLys) but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554109062; hg19: chr6-7585183;