chr9-128627422-CAGG-C

Variant names:

• chr9-128627422-CAGG-C
• rs587784438
• NM_001130438.3:c.6619_6621delGAG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.53
• Publications: 4 publications found

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]

SPTAN1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 160024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTAN1	NM_001130438.3	c.6619_6621delGAG	p.Glu2207del	conservative_inframe_deletion	Exon 50 of 57	ENST00000372739.7	NP_001123910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTAN1	ENST00000372739.7	c.6619_6621delGAG	p.Glu2207del	conservative_inframe_deletion	Exon 50 of 57	1	NM_001130438.3	ENSP00000361824.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 5 Pathogenic:5

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Sep 01, 2017

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Mar 30, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Apr 16, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy Pathogenic:1

Jun 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587784438; hg19: chr9-131389701; COSMIC: COSV63986738; COSMIC: COSV63986738;