chr8-143920178-T-C
Variant summary
Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong
The NM_201384.3(PLEC):c.9643A>G(p.Lys3215Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000707 in 1,611,936 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. K3215R) 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 -4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.9643A>G | p.Lys3215Glu | missense_variant | Exon 32 of 32 | 1 | NM_201384.3 | ENSP00000344848.3 | ||
PLEC | ENST00000356346.7 | c.9601A>G | p.Lys3201Glu | missense_variant | Exon 32 of 32 | 1 | NM_201378.4 | ENSP00000348702.3 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152146Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000832 AC: 20AN: 240400 AF XY: 0.000106 show subpopulations
GnomAD4 exome AF: 0.0000726 AC: 106AN: 1459790Hom.: 0 Cov.: 73 AF XY: 0.0000826 AC XY: 60AN XY: 726198 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74334 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 lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 3242 of the PLEC protein (p.Lys3242Glu). This variant is present in population databases (rs782078326, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PLEC-related conditions. ClinVar contains an entry for this variant (Variation ID: 538971). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamic acid 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. -
not provided Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at