chr8-143925158-G-A
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_201384.3(PLEC):c.4771C>T(p.Gln1591*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,407,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_201384.3 stop_gained
Scores
Clinical Significance
Conservation
Publications
- epidermolysis bullosa simplexInheritance: AD Classification: STRONG Submitted by: G2P
- epidermolysis bullosa simplex 5A, Ogna typeInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Genomics England PanelApp
- autosomal recessive limb-girdle muscular dystrophy type 2QInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
- congenital myasthenic syndromeInheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
- epidermolysis bullosa simplex 5B, with muscular dystrophyInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp
- epidermolysis bullosa simplex 5C, with pyloric atresiaInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- epidermolysis bullosa simplex with nail dystrophyInheritance: AR Classification: STRONG Submitted by: PanelApp Australia
- autosomal recessive limb-girdle muscular dystrophyInheritance: AR Classification: MODERATE Submitted by: ClinGen
- aplasia cutis congenitaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- cholestasisInheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.4771C>T | p.Gln1591* | stop_gained | Exon 31 of 32 | 1 | NM_201384.3 | ENSP00000344848.3 | ||
PLEC | ENST00000356346.7 | c.4729C>T | p.Gln1577* | stop_gained | Exon 31 of 32 | 1 | NM_201378.4 | ENSP00000348702.3 |
Frequencies
GnomAD3 genomes Cov.: 35
GnomAD4 exome AF: 0.00000142 AC: 2AN: 1407386Hom.: 0 Cov.: 68 AF XY: 0.00000143 AC XY: 1AN XY: 697166 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 35
ClinVar
Submissions by phenotype
Epidermolysis bullosa simplex, Ogna type;C2677349:Epidermolysis bullosa simplex 5C, with pyloric atresia;C2931072:Epidermolysis bullosa simplex 5B, with muscular dystrophy;C3150989:Autosomal recessive limb-girdle muscular dystrophy type 2Q;C4225309:Epidermolysis bullosa simplex with nail dystrophy Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gln1618*) in the PLEC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLEC are known to be pathogenic (PMID: 20301336, 20447487, 21109228, 23289980, 28824526). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PLEC-related conditions. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at