NM_001355436.2:c.5266C>T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001355436.2(SPTB):c.5266C>T(p.Arg1756*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001355436.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPTB | NM_001355436.2 | c.5266C>T | p.Arg1756* | stop_gained | Exon 26 of 36 | ENST00000644917.1 | NP_001342365.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPTB | ENST00000644917.1 | c.5266C>T | p.Arg1756* | stop_gained | Exon 26 of 36 | NM_001355436.2 | ENSP00000495909.1 | |||
SPTB | ENST00000553938.5 | c.1261C>T | p.Arg421* | stop_gained | Exon 7 of 18 | 1 | ENSP00000451324.1 | |||
SPTB | ENST00000389722.7 | c.5266C>T | p.Arg1756* | stop_gained | Exon 25 of 35 | 2 | ENSP00000374372.3 | |||
SPTB | ENST00000389720.4 | c.5266C>T | p.Arg1756* | stop_gained | Exon 26 of 32 | 5 | ENSP00000374370.4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1459084Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 725404
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:5
PVS1_strong, PS4, PM2, PS3 -
This sequence change creates a premature translational stop signal (p.Arg1756*) in the SPTB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPTB are known to be pathogenic (PMID: 1391962, 1498324, 8844207, 26830532, 27292444). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary spherocytosis (PMID: 19538529, 26830532, 31602632, 32436265). ClinVar contains an entry for this variant (Variation ID: 12843). For these reasons, this variant has been classified as Pathogenic. -
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The SPTB c.5266C>T; p.Arg1756 variant (rs267607086) is reported in the literature in at least 12 individuals affected with hereditary spherocytosis (Aggarwal 2020, Maciag 2009, Park 2016, Tole 2020). This variant is also reported in ClinVar (Variation ID: 12843). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. -
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 31602632, 19538529, 31980736, 32436265, 37385619, 34335240, 38831725, 27292444, 37205956, 26830532) -
Hereditary spherocytosis type 2 Pathogenic:3
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This nonsense variant found in exon 25 of 35 is predicted to result in loss of normal protein function. This variant has been previously reported as heterozygous change in patients with hereditary spherocytosis (PMID 19538529, 26830532). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.5266C>T, p.Arg1756Ter variant is classified as Pathogenic. -
Elliptocytosis 3;C2674219:Hereditary spherocytosis type 2 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at