rs796053335

chr9-128632280-G-GGCATGC

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_001130438.3(SPTAN1):c.6923_6928dup(p.Arg2308_Met2309dup) variant causes a 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G2306G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPTAN1 NM_001130438.3 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

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain 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/exons	MANE	UniProt
SPTAN1	NM_001130438.3	c.6923_6928dup	p.Arg2308_Met2309dup	inframe_insertion	53/57	ENST00000372739.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTAN1	ENST00000372739.7	c.6923_6928dup	p.Arg2308_Met2309dup	inframe_insertion	53/57	1	NM_001130438.3	P3

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 11, 2010	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP4. -
Likely pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, University of Leipzig Medical Center	Sep 01, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	SPTAN1: PS2, PM2, PM4, PS4:Moderate, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2013	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

Pathogenic, criteria provided, single submitter

clinical testing

Neurogenetics Laboratory - MEYER, AOU Meyer

Nov 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

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;