2-54599152-G-A
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP2BS2
The NM_003128.3(SPTBN1):c.209G>A(p.Arg70His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,614,038 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 1 hom. )
Consequence
SPTBN1
NM_003128.3 missense
NM_003128.3 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 9.94
Genes affected
SPTBN1 (HGNC:11275): (spectrin beta, non-erythrocytic 1) Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. It is composed of two antiparallel dimers of alpha- and beta- subunits. This gene is one member of a family of beta-spectrin genes. The encoded protein contains an N-terminal actin-binding domain, and 17 spectrin repeats which are involved in dimer formation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM1
In a region_of_interest Actin-binding (size 273) in uniprot entity SPTB2_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_003128.3
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPTBN1. . Gene score misZ 4.5424 (greater than the threshold 3.09). Trascript score misZ 5.885 (greater than threshold 3.09). GenCC has associacion of gene with developmental delay, impaired speech, and behavioral abnormalities.
BS2
High AC in GnomAdExome4 at 40 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPTBN1 | NM_003128.3 | c.209G>A | p.Arg70His | missense_variant | 3/36 | ENST00000356805.9 | NP_003119.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPTBN1 | ENST00000356805.9 | c.209G>A | p.Arg70His | missense_variant | 3/36 | 1 | NM_003128.3 | ENSP00000349259.4 | ||
SPTBN1 | ENST00000333896.5 | c.170G>A | p.Arg57His | missense_variant | 2/31 | 1 | ENSP00000334156.5 | |||
SPTBN1 | ENST00000389980.7 | c.209G>A | p.Arg70His | missense_variant | 3/14 | 1 | ENSP00000374630.3 | |||
SPTBN1 | ENST00000615901.4 | c.209G>A | p.Arg70His | missense_variant | 3/38 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152160Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251454Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135902
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461878Hom.: 1 Cov.: 30 AF XY: 0.0000303 AC XY: 22AN XY: 727238
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74330
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 21, 2021 | The c.209G>A (p.R70H) alteration is located in exon 3 (coding exon 2) of the SPTBN1 gene. This alteration results from a G to A substitution at nucleotide position 209, causing the arginine (R) at amino acid position 70 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;T;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;D;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
P;.;.;P
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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