8-143921315-C-T
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_201384.3(PLEC):c.8506G>A(p.Asp2836Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00203 in 1,613,938 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2836H) has been classified as Uncertain significance.
Frequency
Consequence
NM_201384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEC | NM_201384.3 | c.8506G>A | p.Asp2836Asn | missense_variant | 32/32 | ENST00000345136.8 | |
PLEC | NM_201378.4 | c.8464G>A | p.Asp2822Asn | missense_variant | 32/32 | ENST00000356346.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.8506G>A | p.Asp2836Asn | missense_variant | 32/32 | 1 | NM_201384.3 | ||
PLEC | ENST00000356346.7 | c.8464G>A | p.Asp2822Asn | missense_variant | 32/32 | 1 | NM_201378.4 |
Frequencies
GnomAD3 genomes AF: 0.00131 AC: 199AN: 152246Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00156 AC: 388AN: 249230Hom.: 2 AF XY: 0.00161 AC XY: 218AN XY: 135302
GnomAD4 exome AF: 0.00211 AC: 3080AN: 1461574Hom.: 7 Cov.: 78 AF XY: 0.00209 AC XY: 1517AN XY: 727126
GnomAD4 genome AF: 0.00131 AC: 200AN: 152364Hom.: 0 Cov.: 34 AF XY: 0.00130 AC XY: 97AN XY: 74514
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 31, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | PLEC: BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 15, 2015 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PLEC p.Asp2973Asn variant was identified in 1 of 14 proband chromosomes (frequency: 0.071) from individuals with mesial temporal lobe epilepsy (Sha_2015_PMID:25668491). The variant was also identified in dbSNP (ID: rs200814155), ClinVar (classified as a VUS by EGL Genetics, Athena Diagnostics and Invitae and as likely benign by GeneDx), Cosmic (FATHMM predicted pathogenic; score=0.93) and LOVD 3.0. The variant was identified in control databases in 438 of 280620 chromosomes (2 homozygous) at a frequency of 0.001561 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 79 of 35366 chromosomes (freq: 0.002234), European (non-Finnish) in 245 of 128510 chromosomes (freq: 0.001906), Other in 12 of 7140 chromosomes (freq: 0.001681), European (Finnish) in 34 of 25012 chromosomes (freq: 0.001359), South Asian in 37 of 30594 chromosomes (freq: 0.001209), Ashkenazi Jewish in 9 of 10352 chromosomes (freq: 0.000869), African in 16 of 24132 chromosomes (freq: 0.000663), and East Asian in 6 of 19514 chromosomes (freq: 0.000308). The p.Asp2973 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 20, 2021 | The c.8587G>A (p.D2863N) alteration is located in exon 33 (coding exon 32) of the PLEC gene. This alteration results from a G to A substitution at nucleotide position 8587, causing the aspartic acid (D) at amino acid position 2863 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
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 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
PLEC-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 04, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at