rs143166100

Positions:

chr9-128607988-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_001130438.3(SPTAN1):c.4283C>G(p.Ala1428Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000814 in 1,614,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00084 ( 1 hom. )

Consequence

SPTAN1
NM_001130438.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:12

Conservation

PhyloP100: 7.84

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPTAN1. . Gene score misZ 5.523 (greater than the threshold 3.09). Trascript score misZ 7.9287 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 5, developmental and epileptic encephalopathy, West syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.04529336).

BP6

Variant 9-128607988-C-G is Benign according to our data. Variant chr9-128607988-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 196861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128607988-C-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTAN1	NM_001130438.3 linkuse as main transcript	c.4283C>G	p.Ala1428Gly	missense_variant	33/57	ENST00000372739.7	NP_001123910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTAN1	ENST00000372739.7 linkuse as main transcript	c.4283C>G	p.Ala1428Gly	missense_variant	33/57	1	NM_001130438.3	ENSP00000361824	P3	Q13813-2

Frequencies

GnomAD3 genomes

AF:

0.000559

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000573

AC:

144

AN:

251446

Hom.:

AF XY:

0.000625

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000841

AC:

1229

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000818

AC XY:

595

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.00104

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.000558

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00113

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000844

Hom.:

Bravo

AF:

0.000491

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000642

AC:

EpiCase

AF:

0.00125

EpiControl

AF:

0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SPTAN1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2021	This variant is associated with the following publications: (PMID: 29741288, 31515523) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Sep 29, 2023	- -

Developmental and epileptic encephalopathy, 5

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 09, 2022	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 09, 2021	- -

Childhood epilepsy with centrotemporal spikes

Pathogenic:1

Pathogenic, flagged submission

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

SPTAN1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.;.;.;.

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

T;T;T;T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.045

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

L;.;L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.5

N;.;N;.;.

REVEL

Benign

0.076

Sift

Benign

0.079

T;.;T;.;.

Sift4G

Benign

0.064

T;T;T;T;T

Polyphen

0.0050

B;.;B;B;.

Vest4

0.28

MVP

0.35

MPC

0.77

ClinPred

0.035

GERP RS

5.6

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.24

gMVP

0.082

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over