6-7565448-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_004415.4(DSP):​c.867C>T​(p.Cys289Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

DSP
NM_004415.4 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.07

Publications

3 publications found
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 Gene-Disease associations (from GenCC):
  • arrhythmogenic right ventricular dysplasia 8
    Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
  • keratosis palmoplantaris striata 2
    Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
  • skin fragility-woolly hair-palmoplantar keratoderma syndrome
    Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
  • arrhythmogenic cardiomyopathy with wooly hair and keratoderma
    Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
  • cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
  • lethal acantholytic epidermolysis bullosa
    Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
  • familial isolated dilated cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • striate palmoplantar keratoderma
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • severe dermatitis-multiple allergies-metabolic wasting syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hypertrophic cardiomyopathy
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.58).
BP6
Variant 6-7565448-C-T is Benign according to our data. Variant chr6-7565448-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 385121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-1.07 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DSPNM_004415.4 linkc.867C>T p.Cys289Cys synonymous_variant Exon 7 of 24 ENST00000379802.8 NP_004406.2 P15924-1B4DKX6
DSPNM_001319034.2 linkc.867C>T p.Cys289Cys synonymous_variant Exon 7 of 24 NP_001305963.1 P15924-3B4DKX6
DSPNM_001008844.3 linkc.867C>T p.Cys289Cys synonymous_variant Exon 7 of 24 NP_001008844.1 P15924-2B4DKX6Q4LE79
DSPNM_001406591.1 linkc.867C>T p.Cys289Cys synonymous_variant Exon 7 of 11 NP_001393520.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkc.867C>T p.Cys289Cys synonymous_variant Exon 7 of 24 1 NM_004415.4 ENSP00000369129.3 P15924-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251382
AF XY:
0.0000147
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461854
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
727226
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000899
AC:
10
AN:
1111984
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Mar 28, 2016
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Dec 13, 2023
All of Us Research Program, National Institutes of Health
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Nov 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.58
CADD
Benign
0.26
DANN
Benign
0.61
PhyloP100
-1.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=95/5
polymorphism

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

Other links and lift over

dbSNP: rs397516973; hg19: chr6-7565681; COSMIC: COSV101131207; API