6-7575273-CTT-CT

Position:

• chr6-7575273-CTT-CT

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The ENST00000379802.8(DSP):​c.2437-11del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 817,948 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00092 (3 hom., cov: 33)
  • Exomes 𝑓: 0.026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DSP ENST00000379802.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.0620

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 Benign. Variant got -12 ACMG points.

• BP6: Variant 6-7575273-CT-C is Benign according to our data. Variant chr6-7575273-CT-C is described in ClinVar as [Benign]. Clinvar id is 163253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7575273-CT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0259 (21176/817948) while in subpopulation AMR AF= 0.0415 (925/22266). AF 95% confidence interval is 0.0393. There are 0 homozygotes in gnomad4_exome. There are 10511 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.2437-11del		intron_variant		ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3	c.2437-11del		intron_variant			NP_001008844.1
DSP	NM_001319034.2	c.2437-11del		intron_variant			NP_001305963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2437-11del		intron_variant		1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.2437-11del		intron_variant		1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.2437-11del		intron_variant				ENSP00000518230	A2
DSP	ENST00000684395.1	n.1078-11del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00 AC: 121 AN: 147218 Hom.: 0 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000951

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000214

Gnomad FIN AF: 0.00148

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000406

Gnomad OTH AF: 0.000503

GnomAD4 exome AF: 0.0259 AC: 21176 AN: 817948 Hom.: 0 Cov.: 30 AF XY: 0.0260 AC XY: 10511 AN XY: 403684

Gnomad4 AFR exome AF: 0.0321

Gnomad4 AMR exome AF: 0.0415

Gnomad4 ASJ exome AF: 0.0341

Gnomad4 EAS exome AF: 0.0338

Gnomad4 SAS exome AF: 0.0248

Gnomad4 FIN exome AF: 0.0344

Gnomad4 NFE exome AF: 0.0243

Gnomad4 OTH exome AF: 0.0294

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000923 AC: 136 AN: 147288 Hom.: 3 Cov.: 33 AF XY: 0.00100 AC XY: 72 AN XY: 71670

Gnomad4 AFR AF: 0.00196

Gnomad4 AMR AF: 0.000950

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000215

Gnomad4 FIN AF: 0.00148

Gnomad4 NFE AF: 0.000406

Gnomad4 OTH AF: 0.000499

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2013	2437-11delT in intron 17 of DSP: This variant is not expected to have clinical s ignificance because it has been identified in 18% (1498/8254) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS). -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hypertrophic cardiomyopathy 2 Other:1

not provided, no classification provided

clinical testing

Institute of Human Genetics, University of Wuerzburg

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Computational scores

Source: dbNSFP v4.3

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: rs727502998; hg19: chr6-7575506;