rs398124226
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong
The NM_006363.6(SEC23B):c.689+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_006363.6 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SEC23B | NM_006363.6 | c.689+1G>A | splice_donor_variant | ENST00000650089.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SEC23B | ENST00000650089.1 | c.689+1G>A | splice_donor_variant | NM_006363.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251336Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135836
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461774Hom.: 0 Cov.: 35 AF XY: 0.00000963 AC XY: 7AN XY: 727204
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 05, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 05, 2021 | - - |
Congenital dyserythropoietic anemia, type II;C4225179:Cowden syndrome 7 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change affects a donor splice site in intron 6 of the SEC23B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SEC23B are known to be pathogenic (PMID: 19561605, 25044164). This variant is present in population databases (rs398124226, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with congenital dyserythropoietic anemia type II (PMID: 19561605, 19621418). ClinVar contains an entry for this variant (Variation ID: 95389). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Cowden syndrome 7 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 20, 2021 | - - |
Congenital dyserythropoietic anemia, type II Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Apr 02, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PM3. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at