chr9-128632127-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM5PP3BP6_Very_StrongBS1BS2

The NM_001130438.3(SPTAN1):​c.6763C>T​(p.Arg2255Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000106 in 1,612,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2255H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SPTAN1
NM_001130438.3 missense, splice_region

Scores

8
7
4
Splicing: ADA: 0.9954
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.69

Publications

2 publications found
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 Gene-Disease associations (from GenCC):
  • developmental and epileptic encephalopathy, 5
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
  • genetic developmental and epileptic encephalopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • infantile spasms
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-128632128-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1685144.
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
BP6
Variant 9-128632127-C-T is Benign according to our data. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128632127-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 238540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000854 (13/152184) while in subpopulation NFE AF = 0.000176 (12/68040). AF 95% confidence interval is 0.000102. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPTAN1NM_001130438.3 linkc.6763C>T p.Arg2255Cys missense_variant, splice_region_variant Exon 53 of 57 ENST00000372739.7 NP_001123910.1 Q13813-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPTAN1ENST00000372739.7 linkc.6763C>T p.Arg2255Cys missense_variant, splice_region_variant Exon 53 of 57 1 NM_001130438.3 ENSP00000361824.4 Q13813-2

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152184
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000402
AC:
10
AN:
248928
AF XY:
0.0000296
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000357
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000108
AC:
158
AN:
1460730
Hom.:
0
Cov.:
33
AF XY:
0.0000922
AC XY:
67
AN XY:
726680
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33474
American (AMR)
AF:
0.0000447
AC:
2
AN:
44696
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39688
South Asian (SAS)
AF:
0.000116
AC:
10
AN:
86212
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52478
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.000123
AC:
137
AN:
1111908
Other (OTH)
AF:
0.000149
AC:
9
AN:
60374
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.464
Heterozygous variant carriers
0
9
18
26
35
44
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152184
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74332
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41448
American (AMR)
AF:
0.00
AC:
0
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.0000942
AC:
1
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000176
AC:
12
AN:
68040
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000100
Hom.:
0
Bravo
AF:
0.0000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Jun 19, 2017
Eurofins Ntd Llc (ga)
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Benign:1
Dec 03, 2019
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as 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. -

Developmental and epileptic encephalopathy Benign:1
Nov 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

SPTAN1-related disorder Benign:1
Aug 10, 2021
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

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). -

not provided Benign:1
Mar 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

SPTAN1: PP2, BS1, BS2 -

Developmental and epileptic encephalopathy, 5 Benign:1
Jul 15, 2021
Genome-Nilou Lab
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Benign
-0.045
T
BayesDel_noAF
Uncertain
-0.040
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.51
D;.;.;.;.
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.75
D;D;D;D;D
MetaSVM
Benign
-0.37
T
MutationAssessor
Benign
1.7
L;.;.;.;.
PhyloP100
5.7
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-4.5
D;.;D;D;.
REVEL
Uncertain
0.32
Sift
Uncertain
0.0010
D;.;D;D;.
Sift4G
Pathogenic
0.0010
D;D;D;D;D
Polyphen
1.0
D;.;D;D;.
Vest4
0.73
MVP
0.67
MPC
1.1
ClinPred
0.81
D
GERP RS
5.4
Varity_R
0.42
gMVP
0.61
Mutation Taster
=33/67
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.92
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

Other links and lift over

dbSNP: rs372779649; hg19: chr9-131394406; API