chr1-43423096-C-T
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_001365999.1(SZT2):c.2038-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000959 in 1,584,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001365999.1 splice_region, intron
Scores
Clinical Significance
Conservation
Publications
- developmental and epileptic encephalopathy, 18Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
- genetic developmental and epileptic encephalopathyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- undetermined early-onset epileptic encephalopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SZT2 | ENST00000634258.3 | c.2038-3C>T | splice_region_variant, intron_variant | Intron 14 of 71 | 5 | NM_001365999.1 | ENSP00000489255.1 | |||
SZT2 | ENST00000562955.2 | c.2038-3C>T | splice_region_variant, intron_variant | Intron 14 of 70 | 5 | ENSP00000457168.1 | ||||
SZT2 | ENST00000470139.1 | n.769-3C>T | splice_region_variant, intron_variant | Intron 5 of 17 | 2 | ENSP00000492726.1 |
Frequencies
GnomAD3 genomes AF: 0.000539 AC: 82AN: 152166Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000105 AC: 22AN: 209474 AF XY: 0.0000692 show subpopulations
GnomAD4 exome AF: 0.0000496 AC: 71AN: 1431932Hom.: 0 Cov.: 32 AF XY: 0.0000281 AC XY: 20AN XY: 711426 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000532 AC: 81AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43AN XY: 74452 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 18 Uncertain:1
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Inborn genetic diseases Uncertain:1
The c.2038-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from N/A in the SZT2 gene. This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
This sequence change falls in intron 14 of the SZT2 gene. It does not directly change the encoded amino acid sequence of the SZT2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs578153834, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with SZT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 411938). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at