NM_001130438.3:c.6908_6916dupACCAGCTGG

Variant names:

• chr9-128632260-G-GGGACCAGCT
• rs587784440
• NM_001130438.3:c.6908_6916dupACCAGCTGG

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_001130438.3(SPTAN1):​c.6908_6916dupACCAGCTGG​(p.Asp2303_Leu2305dup) 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 (★★). ClinVar reports functional evidence for this variant: "SCV000825175: Experimental studies have shown that this variant affects SPTAN1 function (PMID:29050398)." and additional evidence is available in ClinVar. 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 disruptive_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 9.59
• Publications: 1 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuronopathy, distal hereditary motor, autosomal dominant 11

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spastic paraplegia

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000825175: Experimental studies have shown that this variant affects SPTAN1 function (PMID: 29050398).; SCV004119798: "This variant causes aggregation of spectrin complexes in neurons via dominant-negative effects (Nonoda et al. 2013. PubMed ID: 22656320; Tohyama et al. 2015. PubMed ID: 25631096; Syrbe et al. 2017. PubMed ID: 29050398; Wang et al. 2018. PubMed ID: 29337302)."
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 9-128632260-G-GGGACCAGCT is Pathogenic according to our data. Variant chr9-128632260-G-GGGACCAGCT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 160028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130438.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTAN1	NM_001130438.3	MANE Select	c.6908_6916dupACCAGCTGG	p.Asp2303_Leu2305dup	disruptive_inframe_insertion	Exon 53 of 57	NP_001123910.1	Q13813-2
	SPTAN1	NM_001375318.1		c.7007_7015dupACCAGCTGG	p.Asp2336_Leu2338dup	disruptive_inframe_insertion	Exon 55 of 59	NP_001362247.1
	SPTAN1	NM_001375310.1		c.6995_7003dupACCAGCTGG	p.Asp2332_Leu2334dup	disruptive_inframe_insertion	Exon 54 of 58	NP_001362239.1	A0A994J6W3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTAN1	ENST00000372739.7	TSL:1 MANE Select	c.6908_6916dupACCAGCTGG	p.Asp2303_Leu2305dup	disruptive_inframe_insertion	Exon 53 of 57	ENSP00000361824.4	Q13813-2
	SPTAN1	ENST00000372731.8	TSL:1	c.6893_6901dupACCAGCTGG	p.Asp2298_Leu2300dup	disruptive_inframe_insertion	Exon 52 of 56	ENSP00000361816.4	Q13813-1
	SPTAN1	ENST00000358161.9	TSL:1	c.6833_6841dupACCAGCTGG	p.Asp2278_Leu2280dup	disruptive_inframe_insertion	Exon 51 of 55	ENSP00000350882.6	Q13813-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Developmental and epileptic encephalopathy, 5 (6)
4	-	-	not provided (4)
1	-	-	Developmental and epileptic encephalopathy (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not specified (1)
1	-	-	SPTAN1-related disorder (1)
-	-	-	Undetermined early-onset epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587784440; hg19: chr9-131394539;