chr8-143917415-C-G
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_201384.3(PLEC):c.12406G>C(p.Val4136Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,612,856 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. V4136M) 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.12406G>C | p.Val4136Leu | missense_variant | Exon 32 of 32 | 1 | NM_201384.3 | ENSP00000344848.3 | ||
PLEC | ENST00000356346.7 | c.12364G>C | p.Val4122Leu | missense_variant | Exon 32 of 32 | 1 | NM_201378.4 | ENSP00000348702.3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152114Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000161 AC: 4AN: 248978 AF XY: 0.0000222 show subpopulations
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1460742Hom.: 1 Cov.: 60 AF XY: 0.0000193 AC XY: 14AN XY: 726706 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74300 show subpopulations
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 valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4163 of the PLEC protein (p.Val4163Leu). This variant is present in population databases (rs749212061, gnomAD 0.004%), including at least one homozygous and/or hemizygous individual. 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: 478627). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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