rs201194946
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting
The NM_201384.3(PLEC):c.2410C>T(p.Arg804Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,573,544 control chromosomes in the GnomAD database, including 2 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. R804Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_201384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEC | NM_201384.3 | c.2410C>T | p.Arg804Trp | missense_variant | 20/32 | ENST00000345136.8 | |
PLEC | NM_201378.4 | c.2368C>T | p.Arg790Trp | missense_variant | 20/32 | ENST00000356346.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.2410C>T | p.Arg804Trp | missense_variant | 20/32 | 1 | NM_201384.3 | ||
PLEC | ENST00000356346.7 | c.2368C>T | p.Arg790Trp | missense_variant | 20/32 | 1 | NM_201378.4 |
Frequencies
GnomAD3 genomes ? AF: 0.000210 AC: 32AN: 152196Hom.: 1 Cov.: 34
GnomAD3 exomes AF: 0.000208 AC: 37AN: 178256Hom.: 0 AF XY: 0.000236 AC XY: 23AN XY: 97648
GnomAD4 exome AF: 0.000163 AC: 232AN: 1421230Hom.: 1 Cov.: 36 AF XY: 0.000209 AC XY: 147AN XY: 704134
GnomAD4 genome ? AF: 0.000210 AC: 32AN: 152314Hom.: 1 Cov.: 34 AF XY: 0.000295 AC XY: 22AN XY: 74478
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 07, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PLEC p.Arg831Trp variant was not identified in the literature but was identified in dbSNP (ID: rs201194946) and ClinVar (classified as uncertain significance by Invitae and EGL Genetics). The variant was identified in control databases in 43 of 209598 chromosomes at a frequency of 0.0002052 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 27 of 25362 chromosomes (freq: 0.001065), African in 9 of 18244 chromosomes (freq: 0.000493), Other in 2 of 5848 chromosomes (freq: 0.000342), Latino in 2 of 28652 chromosomes (freq: 0.00007) and European (non-Finnish) in 3 of 89142 chromosomes (freq: 0.000034), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Arg831 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 16, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 27, 2023 | - - |
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
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 831 of the PLEC protein (p.Arg831Trp). This variant is present in population databases (rs201194946, gnomAD 0.1%). 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: 487334). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLEC protein function with a negative predictive value of 80%. 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