chr8-143917997-C-A
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_201384.3(PLEC):c.11824G>T(p.Ala3942Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. A3942T) has been classified as Uncertain significance.
Frequency
Consequence
NM_201384.3 missense
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: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.11824G>T | p.Ala3942Ser | missense_variant | Exon 32 of 32 | 1 | NM_201384.3 | ENSP00000344848.3 | ||
PLEC | ENST00000356346.7 | c.11782G>T | p.Ala3928Ser | missense_variant | Exon 32 of 32 | 1 | NM_201378.4 | ENSP00000348702.3 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152060Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000405 AC: 1AN: 246654 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460148Hom.: 0 Cov.: 56 AF XY: 0.00000138 AC XY: 1AN XY: 726378 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152060Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74272 show subpopulations
Age Distribution
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 Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3969 of the PLEC protein (p.Ala3969Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PLEC-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at