chr6-7585755-G-GGGATCTCGCTCC

Variant names:

• chr6-7585755-G-GGGATCTCGCTCC
• rs397516971
• NM_004415.4:c.8508_8519dupATCTCGCTCCGG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM4 PP3

The NM_004415.4(DSP):​c.8508_8519dupATCTCGCTCCGG​(p.Gly2840_Ser2841insSerArgSerGly) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,609,456 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G2840G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: DSP NM_004415.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 8.12

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 3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_004415.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.8508_8519dupATCTCGCTCCGG	p.Gly2840_Ser2841insSerArgSerGly	disruptive_inframe_insertion	Exon 24 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.7179_7190dupATCTCGCTCCGG	p.Gly2397_Ser2398insSerArgSerGly	disruptive_inframe_insertion	Exon 24 of 24		NP_001305963.1
DSP	NM_001008844.3	c.6711_6722dupATCTCGCTCCGG	p.Gly2241_Ser2242insSerArgSerGly	disruptive_inframe_insertion	Exon 24 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.8508_8519dupATCTCGCTCCGG	p.Gly2840_Ser2841insSerArgSerGly	disruptive_inframe_insertion	Exon 24 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.6711_6722dupATCTCGCTCCGG	p.Gly2241_Ser2242insSerArgSerGly	disruptive_inframe_insertion	Exon 24 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.7179_7190dupATCTCGCTCCGG	p.Gly2397_Ser2398insSerArgSerGly	disruptive_inframe_insertion	Exon 24 of 24			ENSP00000518230.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000567 AC: 14 AN: 246768 Hom.: 0 AF XY: 0.0000747 AC XY: 10 AN XY: 133792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000922

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000384 AC: 56 AN: 1457366 Hom.: 0 Cov.: 33 AF XY: 0.0000400 AC XY: 29 AN XY: 724800

Gnomad4 AFR exome AF: 0.0000903

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.000579

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74304

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.8508_8519dup, results in the insertion of 4 amino acid(s) of the DSP protein (p.Ser2843_Arg2846dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs773419695, gnomAD 0.09%). This variant has been observed in individual(s) with clinical features of DSP-related conditions (PMID: 33652119). ClinVar contains an entry for this variant (Variation ID: 848944). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiomyopathy Uncertain:1

Dec 21, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a duplication of 4-amino-acid motif (Ser-Gly-Ser-Arg) in the C-terminal region of the DSP protein that contains 5 consecutive repeats of the Ser-Gly-Ser-Arg motif. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a survivor of sudden cardiac arrest (PMID: 33652119). This variant has been identified in 16/278122 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

May 07, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame insertion of 4 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype Uncertain:1

Apr 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8508_8519dup12 variant (also known as p.S2843_R2846dup), located in coding exon 24 of the DSP gene, results from an in-frame duplication of 12 nucleotides at nucleotide positions 8508 to 8519. This results in the duplication of 4 extra residues (SGSR) between codons 2843 and 2846. This amino acid region is highly conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear. -

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: rs397516971; hg19: chr6-7585988;