rs727504145
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_006363.6(SEC23B):c.1489C>T(p.Arg497Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,086 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R497L) has been classified as Uncertain significance.
Frequency
Consequence
NM_006363.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SEC23B | NM_006363.6 | c.1489C>T | p.Arg497Cys | missense_variant | 13/20 | ENST00000650089.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SEC23B | ENST00000650089.1 | c.1489C>T | p.Arg497Cys | missense_variant | 13/20 | NM_006363.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152240Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251434Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135890
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461846Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727216
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152240Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74374
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 23, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 28, 2023 | - - |
Congenital dyserythropoietic anemia, type II;C4225179:Cowden syndrome 7 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 497 of the SEC23B protein (p.Arg497Cys). This variant is present in population databases (rs727504145, gnomAD 0.006%). This missense change has been observed in individual(s) with congenital dyserythropoietic anemia type II (PMID: 19561605, 19621418, 20015893, 27471141). ClinVar contains an entry for this variant (Variation ID: 167667). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SEC23B protein function. For these reasons, this variant has been classified as Pathogenic. - |
Congenital dyserythropoietic anemia, type II Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 31, 2018 | The SEC23B c.1489C>T (p.Arg497Cys) variant has been reported in five studies and in a total of nine individuals with dyserythropoietic anemia including one individual in a homozygous state and eight individuals in a compound heterozygous state (Schwarz et al. 2009, Bianchi et al. 2009, Iolascon et al. 2010, Russo et al. 2010, Russo et al. 2013). The variant was absent from 407 controls and is reported at a frequency of 0.000032 in the European (non-Finnish) population of the Genome Aggregation Database. The Arg497 amino acid residue is conserved among several species. Based on the evidence, the p.Arg497Cys variant is classified as pathogenic for congenital dyserythropoietic anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at