rs759451802
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP2PP3BP6
The NM_006946.4(SPTBN2):c.964G>A(p.Glu322Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
SPTBN2
NM_006946.4 missense
NM_006946.4 missense
Scores
2
8
8
Clinical Significance
Conservation
PhyloP100: 4.95
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 Uncertain_significance. Variant got 1 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, SPTBN2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.764
BP6
?
Variant 11-66710691-C-T is Benign according to our data. Variant chr11-66710691-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448528.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPTBN2 | NM_006946.4 | c.964G>A | p.Glu322Lys | missense_variant | 10/38 | ENST00000533211.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPTBN2 | ENST00000533211.6 | c.964G>A | p.Glu322Lys | missense_variant | 10/38 | 5 | NM_006946.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251224Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135886
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GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727224
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74340
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 02, 2023 | The c.964G>A (p.E322K) alteration is located in exon 9 (coding exon 8) of the SPTBN2 gene. This alteration results from a G to A substitution at nucleotide position 964, causing the glutamic acid (E) at amino acid position 322 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 04, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Pathogenic
DEOGEN2
Benign
T;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;L;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;D;.
REVEL
Uncertain
Sift
Benign
T;T;.;T;.
Sift4G
Benign
T;T;T;T;T
Polyphen
D;D;.;.;.
Vest4
MutPred
Gain of ubiquitination at E322 (P = 0.0114);Gain of ubiquitination at E322 (P = 0.0114);Gain of ubiquitination at E322 (P = 0.0114);Gain of ubiquitination at E322 (P = 0.0114);Gain of ubiquitination at E322 (P = 0.0114);
MVP
MPC
ClinPred
D
GERP RS
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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