rs587784438
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_001130438.3(SPTAN1):c.6619_6621delGAG(p.Glu2207del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
SPTAN1
NM_001130438.3 conservative_inframe_deletion
NM_001130438.3 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.53
Genes affected
SPTAN1 (HGNC:11273): (spectrin alpha, non-erythrocytic 1) Spectrins are a family of filamentous cytoskeletal proteins that function as essential scaffold proteins that stabilize the plasma membrane and organize intracellular organelles. Spectrins are composed of alpha and beta dimers that associate to form tetramers linked in a head-to-head arrangement. This gene encodes an alpha spectrin that is specifically expressed in nonerythrocytic cells. The encoded protein has been implicated in other cellular functions including DNA repair and cell cycle regulation. Mutations in this gene are the cause of early infantile epileptic encephalopathy-5. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Sep 2010]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001130438.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 9-128627422-CAGG-C is Pathogenic according to our data. Variant chr9-128627422-CAGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 160024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128627422-CAGG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPTAN1 | NM_001130438.3 | c.6619_6621delGAG | p.Glu2207del | conservative_inframe_deletion | 50/57 | ENST00000372739.7 | NP_001123910.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPTAN1 | ENST00000372739.7 | c.6619_6621delGAG | p.Glu2207del | conservative_inframe_deletion | 50/57 | 1 | NM_001130438.3 | ENSP00000361824.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 5 Pathogenic:5
Likely pathogenic, criteria provided, single submitter | research | Institute of Human Genetics, University of Leipzig Medical Center | Sep 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 5 (MIM#613477). Both missense variants and inframe deletions/duplications variants have been demonstrated to impair wildtype protein function (PMID: 20493457). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. However, this is a rare occurrence (PMID: 32811770). (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated nucleation site of the a/b spectrin heterodimer region (PMID: 29050398). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic many times, and has been observed in multiple individuals with infantile epileptic encephalopathy or West syndrome with severe cerebral hypomyelination, spastic quadriplegia and developmental delay. In several of these individuals, the variant was confirmed to be de novo (ClinVar, PMID: 29050398, PMID: 20493457). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Fibroblasts from affected individuals and transfected mouse corticol neurons have both demonstrated protein aggregation and impaired wildtype protein function (PMID: 29050398, PMID: 20493457). (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 - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2012 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2024 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-frame deletion of one amino acid in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25631096, 20493457, 22429196, 29655203, 34489640, 35982159, 36331550, 33057194, 22258530) - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 16, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect SPTAN1 protein function (PMID: 20493457, 22258530). This variant has been observed in individual(s) with early infantile epileptic encephalopathy or West syndrome (PMID: 22429196, 29050398, 20493457). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 160024). This variant is not present in population databases (ExAC no frequency). This variant, c.6619_6621del, results in the deletion of 1 amino acid(s) of the SPTAN1 protein (p.Glu2207del), but otherwise preserves the integrity of the reading frame. - |
SPTAN1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 18, 2024 | The SPTAN1 c.6619_6621delGAG variant is predicted to result in an in-frame deletion (p.Glu2207del). This variant was reported in individuals with West syndrome & cerebral hypomyelination/epilepsy (Saitsu et al 2010. PubMed ID: 20493457; reported as de novo c.6614_c.6616delAGG in Table S2, Lindy et al 2018. PubMed ID: 29655203). Functional studies suggest that .6619_6621delGAG led to abnormal aggregation of spectrin heterodimer (Saitsu et al 2010. PubMed ID: 20493457). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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