11-66704629-G-A
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BS2_Supporting
The NM_006946.4(SPTBN2):c.2647C>T(p.Arg883Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000521 in 1,612,006 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000053 ( 2 hom. )
Consequence
SPTBN2
NM_006946.4 missense
NM_006946.4 missense
Scores
1
5
12
Clinical Significance
Conservation
PhyloP100: 3.92
Genes affected
SPTBN2 (HGNC:11276): (spectrin beta, non-erythrocytic 2) Spectrins are principle components of a cell's membrane-cytoskeleton and are composed of two alpha and two beta spectrin subunits. The protein encoded by this gene (SPTBN2), is called spectrin beta non-erythrocytic 2 or beta-III spectrin. It is related to, but distinct from, the beta-II spectrin gene which is also known as spectrin beta non-erythrocytic 1 (SPTBN1). SPTBN2 regulates the glutamate signaling pathway by stabilizing the glutamate transporter EAAT4 at the surface of the plasma membrane. Mutations in this gene cause a form of spinocerebellar ataxia, SCA5, that is characterized by neurodegeneration, progressive locomotor incoordination, dysarthria, and uncoordinated eye movements. [provided by RefSeq, Dec 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PP2
Missense variant where missense usually causes diseases, SPTBN2
BP4
Computational evidence support a benign effect (MetaRNN=0.27514702).
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPTBN2 | NM_006946.4 | c.2647C>T | p.Arg883Cys | missense_variant | 15/38 | ENST00000533211.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPTBN2 | ENST00000533211.6 | c.2647C>T | p.Arg883Cys | missense_variant | 15/38 | 5 | NM_006946.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151880Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000660 AC: 16AN: 242556Hom.: 0 AF XY: 0.0000606 AC XY: 8AN XY: 132080
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GnomAD4 exome AF: 0.0000527 AC: 77AN: 1460126Hom.: 2 Cov.: 73 AF XY: 0.0000496 AC XY: 36AN XY: 726242
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GnomAD4 genome AF: 0.0000461 AC: 7AN: 151880Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 5AN XY: 74168
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2021 | The c.2647C>T (p.R883C) alteration is located in exon 14 (coding exon 13) of the SPTBN2 gene. This alteration results from a C to T substitution at nucleotide position 2647, causing the arginine (R) at amino acid position 883 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;N
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
D;D;D
Sift4G
Uncertain
T;T;T
Polyphen
D;D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at