rs2806234

chr6-7563750-G-Achr6-7563750-G-Cchr6-7563750-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_004415.4(DSP):c.741G>A(p.Ala247=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,613,434 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A247A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.83

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 6-7563750-G-A is Benign according to our data. Variant chr6-7563750-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7563750-G-A is described in Lovd as [Benign]. Variant chr6-7563750-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.83 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.741G>A	p.Ala247=	synonymous_variant	6/24	ENST00000379802.8
DSP	NM_001319034.2	c.741G>A	p.Ala247=	synonymous_variant	6/24
DSP	NM_001008844.3	c.741G>A	p.Ala247=	synonymous_variant	6/24
DSP	NM_001406591.1	c.741G>A	p.Ala247=	synonymous_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.741G>A	p.Ala247=	synonymous_variant	6/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.741G>A	p.Ala247=	synonymous_variant	6/24	1		A2
DSP	ENST00000710359.1	c.741G>A	p.Ala247=	synonymous_variant	6/24			A2
DSP	ENST00000506617.1	n.259G>A		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.000776 AC: 118 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00129 AC: 1892 AN: 1461316 Hom.: 5 Cov.: 30 AF XY: 0.00124 AC XY: 901 AN XY: 727016

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00158

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000776 AC: 118 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000619 AC XY: 46 AN XY: 74308

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00762 Hom.: 52

Bravo AF: 0.000759

EpiCase AF: 0.00131

EpiControl AF: 0.00124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 15, 2019	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 22, 2019	The p.Ala247Ala variant (c.741T>A) represents a reference sequence error. It is classified as benign because it does not alter an amino acid residue and has been identified in 0.14% (173/126656) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). ACMG/AMP Criteria applied: BA1, BP4, BP7. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 30, 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. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	DSP: BP4, BP7 -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 05, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	1.1

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: rs2806234; hg19: chr6-7563983;