9-128632280-G-GGCATGC

Variant names:

• chr9-128632280-G-GGCATGC
• rs796053335
• NM_001130438.3:c.6923_6928dupGCATGC

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_001130438.3(SPTAN1):​c.6923_6928dupGCATGC​(p.Arg2308_Met2309dup) variant causes a disruptive inframe insertion 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: 33)
• Consequence: SPTAN1 NM_001130438.3 disruptive_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.59

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]

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a repeat Spectrin 20 (size 104) in uniprot entity SPTN1_HUMAN there are 16 pathogenic changes around while only 6 benign (73%) in NM_001130438.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001130438.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 9-128632280-G-GGCATGC is Pathogenic according to our data. Variant chr9-128632280-G-GGCATGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207370.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.6923_6928dupGCATGC	p.Arg2308_Met2309dup	disruptive_inframe_insertion	Exon 53 of 57	ENST00000372739.7	NP_001123910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTAN1	ENST00000372739.7	c.6923_6928dupGCATGC	p.Arg2308_Met2309dup	disruptive_inframe_insertion	Exon 53 of 57	1	NM_001130438.3	ENSP00000361824.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 5 Pathogenic:3

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP4. -

Jun 11, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 01, 2017

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:2

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SPTAN1: PS2, PM2, PM4, PS4:Moderate, PP4 -

Aug 27, 2013

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.6923_6928dupGCATGC: p.Arg2308_Met2309dup (R2308_M2309dup) in exon 53 of the SPTAN1 gene (NM_001130438.1). The normal sequence with the bases that are duplicated in braces is: CATG{CGCATG}. The c.6923_6928dupGCATGC mutation in the SPTAN1 gene has been previously reported as a de novo mutation in an individual with early-onset West syndrome and cerebellar hypomyelination (Saitsu et al., 2010). It results in an in-frame duplication of two highly conserved amino acids in the last spectrin repeat of the protein, and functional studies indicate the c.6923_6928dupGCATGC mutation leads to the aggregation of alpha/beta spectrin heterodimers (Saitsu et al., 2010). Therefore, c.6923_6928dupGCATGC is interpreted as pathogenic. The variant is found in INFANT-EPI panel(s). -

Epileptic encephalopathy Pathogenic:1

Nov 16, 2016

Neurogenetics Laboratory - MEYER, AOU Meyer

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs796053335; hg19: chr9-131394559;