6-145635283-G-A
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2
The NM_005670.4(EPM2A):c.680C>T(p.Ala227Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,614,150 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A227A) has been classified as Likely benign.
Frequency
Consequence
NM_005670.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EPM2A | NM_005670.4 | c.680C>T | p.Ala227Val | missense_variant | 3/4 | ENST00000367519.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EPM2A | ENST00000367519.9 | c.680C>T | p.Ala227Val | missense_variant | 3/4 | 1 | NM_005670.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000861 AC: 131AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00117 AC: 294AN: 251418Hom.: 2 AF XY: 0.00109 AC XY: 148AN XY: 135870
GnomAD4 exome AF: 0.00123 AC: 1798AN: 1461850Hom.: 5 Cov.: 31 AF XY: 0.00120 AC XY: 872AN XY: 727228
GnomAD4 genome AF: 0.000860 AC: 131AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.000765 AC XY: 57AN XY: 74462
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The EPM2A p.Ala227Val variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs147399860) and ClinVar (classified as uncertain significance by EGL Genetics, Ambry Genetics and Invitae, and as likely benign by GeneDx and Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics). The variant was identified in control databases in 317 of 282824 chromosomes (2 homozygous) at a frequency of 0.001121 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 13 of 7222 chromosomes (freq: 0.0018), European (non-Finnish) in 224 of 129136 chromosomes (freq: 0.001735), Latino in 52 of 35438 chromosomes (freq: 0.001467), Ashkenazi Jewish in 9 of 10368 chromosomes (freq: 0.000868), South Asian in 11 of 30616 chromosomes (freq: 0.000359), African in 4 of 24966 chromosomes (freq: 0.00016) and European (Finnish) in 4 of 25124 chromosomes (freq: 0.000159), but was not observed in the East Asian population. The p.Ala227 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 05, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 21, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 04, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 10, 2019 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 28, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
EPM2A-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 30, 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). - |
Intellectual disability Benign:1
Likely benign, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
Progressive myoclonic epilepsy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at