chr9-128566814-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_001130438.3(SPTAN1):​c.74G>A​(p.Arg25Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SPTAN1
NM_001130438.3 missense

Scores

6
7
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.54
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 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.
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SPTAN1NM_001130438.3 linkuse as main transcriptc.74G>A p.Arg25Gln missense_variant 2/57 ENST00000372739.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SPTAN1ENST00000372739.7 linkuse as main transcriptc.74G>A p.Arg25Gln missense_variant 2/571 NM_001130438.3 P3Q13813-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461876
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 11, 2022ClinVar contains an entry for this variant (Variation ID: 976180). This variant has not been reported in the literature in individuals affected with SPTAN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 25 of the SPTAN1 protein (p.Arg25Gln). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Developmental and epileptic encephalopathy, 5 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJul 12, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Uncertain
0.091
D
BayesDel_noAF
Benign
-0.11
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.48
T;.;T;.;.;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D
M_CAP
Benign
0.038
D
MetaRNN
Uncertain
0.58
D;D;D;D;D;D
MetaSVM
Benign
-0.79
T
MutationAssessor
Uncertain
2.4
M;.;.;M;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.79
T
PROVEAN
Uncertain
-2.8
D;.;.;D;D;.
REVEL
Benign
0.21
Sift
Benign
0.078
T;.;.;T;T;.
Sift4G
Uncertain
0.044
D;D;T;D;D;D
Polyphen
0.98
D;.;.;D;D;.
Vest4
0.73
MutPred
0.50
Loss of catalytic residue at R25 (P = 0.0247);Loss of catalytic residue at R25 (P = 0.0247);.;Loss of catalytic residue at R25 (P = 0.0247);Loss of catalytic residue at R25 (P = 0.0247);Loss of catalytic residue at R25 (P = 0.0247);
MVP
0.68
MPC
1.9
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.67
gMVP
0.60

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.

Other links and lift over

dbSNP: rs1850091477; hg19: chr9-131329093; API