5-157294834-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001037333.3(CYFIP2):c.259C>T(p.Arg87Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R87H) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
CYFIP2
NM_001037333.3 missense
NM_001037333.3 missense
Scores
10
3
3
Clinical Significance
Conservation
PhyloP100: 6.85
Genes affected
CYFIP2 (HGNC:13760): (cytoplasmic FMR1 interacting protein 2) Predicted to enable small GTPase binding activity. Involved in activation of cysteine-type endopeptidase activity; apoptotic process; and cell-cell adhesion. Located in perinuclear region of cytoplasm and synapse. Part of SCAR complex. Implicated in developmental and epileptic encephalopathy 65. [provided by Alliance of Genome Resources, Apr 2022]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr5-157294835-G-A is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CYFIP2. . Gene score misZ 6.0129 (greater than the threshold 3.09). Trascript score misZ 6.9267 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 65, developmental and epileptic encephalopathy, 76, undetermined early-onset epileptic encephalopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.948
PP5
Variant 5-157294834-C-T is Pathogenic according to our data. Variant chr5-157294834-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-157294834-C-T is described in Lovd as [Likely_pathogenic]. Variant chr5-157294834-C-T is described in Lovd as [Likely_pathogenic]. Variant chr5-157294834-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CYFIP2 | NM_001037333.3 | c.259C>T | p.Arg87Cys | missense_variant | 4/31 | ENST00000620254.5 | NP_001032410.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CYFIP2 | ENST00000620254.5 | c.259C>T | p.Arg87Cys | missense_variant | 4/31 | 1 | NM_001037333.3 | ENSP00000479968.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 65 Pathogenic:8
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 17, 2020 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jul 03, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | May 13, 2019 | This variant was identified as de novo (maternity and paternity confirmed). - |
| Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Oct 15, 2018 | This variant is interpreted as Likely Pathogenic, for Epileptic encephalopathy, early infantile, 65, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS2 => De novo (paternity and maternity confirmed) (https://www.ncbi.nlm.nih.gov/pubmed/29534297). PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (https://www.ncbi.nlm.nih.gov/pubmed/29534297). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jul 22, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 29534297). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000430807 / PMID: 29534297). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29534297). Different missense changes at the same codon (p.Arg87His, p.Arg87Leu, p.Arg87Pro, p.Arg87Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000545427, VCV000545429, VCV000802171 / PMID: 29534297, 33149277). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 09, 2024 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 65 (MIM#618008). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 33149277). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (PMID: 2953497). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is one of the most commonly reported pathogenic variants in CYFIP2 associated with epileptic encephalopathy; individuals with variants occurring at the p.(Arg87) residue have been consistently reported with a more severe phenotype compared to other pathogenic variants in this gene (ClinVar, PMIDs: 2953497, 33149277). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 15, 2018 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 87 of the CYFIP2 protein (p.Arg87Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CYFIP2-related conditions (PMID: 29534297, 29667327, 30664714). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 430807). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects CYFIP2 function (PMID: 29534297). For these reasons, this variant has been classified as Pathogenic. - |
Seizure Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Apr 24, 2020 | Absent from public databases. Considered pathogenic by prediction scores. de novo - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T;.;T;T;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;.;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.;.;.;M
PrimateAI
Pathogenic
D
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
D;D;.;.;.;.;D
Vest4
MutPred
Loss of MoRF binding (P = 8e-04);Loss of MoRF binding (P = 8e-04);Loss of MoRF binding (P = 8e-04);Loss of MoRF binding (P = 8e-04);Loss of MoRF binding (P = 8e-04);Loss of MoRF binding (P = 8e-04);Loss of MoRF binding (P = 8e-04);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at