rs606231293

Variant names:

• chr6-7571496-G-GCGGAAAATACAGTCTCAGTTCACCGATGCC
• rs606231293
• NM_004415.4:c.1817_1846dupGGAAAATACAGTCTCAGTTCACCGATGCCC

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_1846dupGGAAAATACAGTCTCAGTTCACCGATGCCC​(p.Arg606_Ala615dup) variant causes a disruptive 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). Synonymous variant affecting the same amino acid position (i.e. Q616Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 disruptive_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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain 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 rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.1817_1846dupGGAAAATACAGTCTCAGTTCACCGATGCCC	p.Arg606_Ala615dup	disruptive_inframe_insertion	Exon 14 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1817_1846dupGGAAAATACAGTCTCAGTTCACCGATGCCC	p.Arg606_Ala615dup	disruptive_inframe_insertion	Exon 14 of 24		NP_001305963.1
DSP	NM_001008844.3	c.1817_1846dupGGAAAATACAGTCTCAGTTCACCGATGCCC	p.Arg606_Ala615dup	disruptive_inframe_insertion	Exon 14 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1817_1846dupGGAAAATACAGTCTCAGTTCACCGATGCCC	p.Arg606_Ala615dup	disruptive_inframe_insertion	Exon 14 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1817_1846dupGGAAAATACAGTCTCAGTTCACCGATGCCC	p.Arg606_Ala615dup	disruptive_inframe_insertion	Exon 14 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1817_1846dupGGAAAATACAGTCTCAGTTCACCGATGCCC	p.Arg606_Ala615dup	disruptive_inframe_insertion	Exon 14 of 24			ENSP00000518230.1
DSP	ENST00000684395.1	n.201_230dupGGAAAATACAGTCTCAGTTCACCGATGCCC		non_coding_transcript_exon_variant	Exon 2 of 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

Jul 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;