rs606231293

chr6-7571496-G-GCGGAAAATACAGTCTCAGTTCACCGATGCC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP5

The NM_004415.4(DSP):c.1817_1846dup(p.Arg606_Ala615dup) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.91

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 helix (size 22) in uniprot entity DESP_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_004415.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004415.4.
• PP5: Variant 6-7571496-G-GCGGAAAATACAGTCTCAGTTCACCGATGCC is Pathogenic according to our data. Variant chr6-7571496-G-GCGGAAAATACAGTCTCAGTTCACCGATGCC is described in ClinVar as [Pathogenic]. Clinvar id is 157671.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.1817_1846dup	p.Arg606_Ala615dup	inframe_insertion	14/24	ENST00000379802.8
DSP	NM_001008844.3	c.1817_1846dup	p.Arg606_Ala615dup	inframe_insertion	14/24
DSP	NM_001319034.2	c.1817_1846dup	p.Arg606_Ala615dup	inframe_insertion	14/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.1817_1846dup	p.Arg606_Ala615dup	inframe_insertion	14/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.1817_1846dup	p.Arg606_Ala615dup	inframe_insertion	14/24	1		A2
DSP	ENST00000710359.1	c.1817_1846dup	p.Arg606_Ala615dup	inframe_insertion	14/24			A2
DSP	ENST00000684395.1	n.201_230dup		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2006

- -

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: rs606231293; hg19: chr6-7571729;