chr6-7576336-T-C

Position:

• chr6-7576336-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000379802.8(DSP):​c.2673T>C​(p.Tyr891=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,614,156 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (5 hom.)
• Consequence: DSP ENST00000379802.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.962

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 6-7576336-T-C is Benign according to our data. Variant chr6-7576336-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 44878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7576336-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00641 (976/152358) while in subpopulation AFR AF= 0.0226 (942/41592). AF 95% confidence interval is 0.0214. There are 9 homozygotes in gnomad4. There are 428 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.2673T>C	p.Tyr891=	synonymous_variant	19/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.2673T>C	p.Tyr891=	synonymous_variant	19/24		NP_001305963.1
DSP	NM_001008844.3	c.2673T>C	p.Tyr891=	synonymous_variant	19/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2673T>C	p.Tyr891=	synonymous_variant	19/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.2673T>C	p.Tyr891=	synonymous_variant	19/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.2673T>C	p.Tyr891=	synonymous_variant	19/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes AF: 0.00642 AC: 977 AN: 152240 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

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: 0.00430

GnomAD3 exomes AF: 0.00170 AC: 427 AN: 251276 Hom.: 1 AF XY: 0.00116 AC XY: 157 AN XY: 135804

Gnomad AFR exome AF: 0.0242

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000642 AC: 938 AN: 1461798 Hom.: 5 Cov.: 34 AF XY: 0.000576 AC XY: 419 AN XY: 727198

Gnomad4 AFR exome AF: 0.0245

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00641 AC: 976 AN: 152358 Hom.: 9 Cov.: 33 AF XY: 0.00574 AC XY: 428 AN XY: 74500

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00339 Hom.: 2

Bravo AF: 0.00681

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Tyr891Tyr in Exon 19 of DSP: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 2.3% (87/3738) of Afri can American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs146407262). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 07, 2017	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 22, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 19, 2016	Variant summary: The DSP c.2673T>C (p.Tyr891Tyr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 257/121370 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0239654 (249/10390). This frequency is about 959 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories have classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as Benign. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Woolly hair-skin fragility syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Epidermolysis bullosa simplex due to plakophilin deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.96
DANN	Benign	0.32

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: rs146407262; hg19: chr6-7576569;