rs1060500615

Positions:

chr6-7577834-T-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The ENST00000379802.8(DSP):c.2933T>A(p.Ile978Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I978V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

DSP
ENST00000379802.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 5.95

Variant links:

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]

DSP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP6

Variant 6-7577834-T-A is Benign according to our data. Variant chr6-7577834-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405241.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSP	NM_004415.4 linkuse as main transcript	c.2933T>A	p.Ile978Lys	missense_variant	21/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2 linkuse as main transcript	c.2933T>A	p.Ile978Lys	missense_variant	21/24		NP_001305963.1
DSP	NM_001008844.3 linkuse as main transcript	c.2933T>A	p.Ile978Lys	missense_variant	21/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.2933T>A	p.Ile978Lys	missense_variant	21/24	1	NM_004415.4	ENSP00000369129	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.2933T>A	p.Ile978Lys	missense_variant	21/24	1		ENSP00000396591	A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.2933T>A	p.Ile978Lys	missense_variant	21/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251460

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000163

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 10, 2016	p.Ile978Lys (c.2933T>A) in the DSP gene (NM_004415.2) The lab classifies this variant as a variant of unknown significance. Given a lack of case data we consider this variant a variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been previously reported in the literature. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 0.942) and mutation taster predicts the variant to be disease causing (0.999). The lysine at codon 978 is conserved across close species, but the UCSC geneome browser reports the T at the position is not well conserved in other species suggesting there may be lack of conservation beyond the eight species reported in the mutation taster database. The nearest missense pathogenic or likely pathogenic entries into clinvar are at codons 895 987 and 1601. The variant resides at the end of the globular 1 domain of the desmoplakin domain which includes the first 1056 amino acids of the protein. Kapplinger et al., 2011 from Ackerman's group have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, 16% of 427 controls hosted missense variants-similar to the 21% yield in 175 Dutch and unit(s).S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC related genes need to be interpreted with cation. Kapplinger et al. Also report a "hot spot" for DSP variants between amino acids 250-604 in patients with ARVC but not in controls. In total the variant has not been seen in laboratory controls, published controls and individuals from publicly available population datasets. There are three individuals with p.Ile978Lys and two individuals with p.Ile978Val at codon 978 listed in the gnomAD dataset (http://gnomad.broadinstitute.org/). gnomAD currently includes variant calls on ~126,000 individuals of European, African, Latino and Asian descent (as of November 10, 2016). The average coverage at that site in gnomAD is around 50x. -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 19, 2023

This missense variant replaces isoleucine with lysine at codon 978 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 3/251460 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The p.I978K variant (also known as c.2933T>A), located in coding exon 21 of the DSP gene, results from a T to A substitution at nucleotide position 2933. The isoleucine at codon 978 is replaced by lysine, an amino acid with dissimilar properties. This variant co-occurred with an MYH7 variant in an individual from a dilated cardiomyopathy cohort (Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Uncertain

0.42

T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.53

D;D

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.0

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.015

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.71

MutPred

0.46

Loss of stability (P = 0.0101);Loss of stability (P = 0.0101);

MVP

0.88

MPC

1.1

ClinPred

0.54

GERP RS

5.5

Varity_R

0.22

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over