chr6-7577859-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_004415.4(DSP):c.2958G>T(p.Gln986His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q986P) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
DSP
NM_004415.4 missense
NM_004415.4 missense
Scores
4
11
4
Clinical Significance
Conservation
PhyloP100: 4.75
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.2958G>T | p.Gln986His | missense_variant | 21/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.2958G>T | p.Gln986His | missense_variant | 21/24 | ||
DSP | NM_001008844.3 | c.2958G>T | p.Gln986His | missense_variant | 21/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.2958G>T | p.Gln986His | missense_variant | 21/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.2958G>T | p.Gln986His | missense_variant | 21/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.2958G>T | p.Gln986His | missense_variant | 21/24 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461812Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727214
GnomAD4 exome
AF:
AC:
4
AN:
1461812
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727214
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Alfa
AF:
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Bravo
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 18, 2021 | The p.Q986H variant (also known as c.2958G>T), located in coding exon 21 of the DSP gene, results from a G to T substitution at nucleotide position 2958. The glutamine at codon 986 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort; however, clinical details are limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of catalytic residue at S987 (P = 0.0966);Gain of catalytic residue at S987 (P = 0.0966);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at