15-89776664-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000341735.5(MESP2):c.307G>T(p.Glu103Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000462 in 1,538,410 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E103E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000341735.5 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/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MESP2 | NM_001039958.2 | c.307G>T | p.Glu103Ter | stop_gained | 1/2 | ENST00000341735.5 | NP_001035047.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MESP2 | ENST00000341735.5 | c.307G>T | p.Glu103Ter | stop_gained | 1/2 | 1 | NM_001039958.2 | ENSP00000342392 | P1 | |
MESP2 | ENST00000560219.2 | c.31-1401G>T | intron_variant | 1 | ENSP00000452998 | |||||
MESP2 | ENST00000558723.1 | n.39-1401G>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 152256Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000411 AC: 6AN: 146096Hom.: 0 AF XY: 0.0000243 AC XY: 2AN XY: 82306
GnomAD4 exome AF: 0.0000325 AC: 45AN: 1386042Hom.: 1 Cov.: 30 AF XY: 0.0000233 AC XY: 16AN XY: 686038
GnomAD4 genome AF: 0.000171 AC: 26AN: 152368Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15AN XY: 74508
ClinVar
Submissions by phenotype
Spondylocostal dysostosis 2, autosomal recessive Pathogenic:3
Pathogenic, no assertion criteria provided | curation | GeneReviews | Aug 05, 2010 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2008 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2018 | The E103X variant in the MESP2 gene has been reported previously as a founder variant in the Puerto Rican population and has been observed frequently in the homozygous and compound heterozygous states in individuals with spondylothoracic dysostosis (STD) (Cornier et al., 2008). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The E103X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret E103X as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Glu103*) in the MESP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MESP2 are known to be pathogenic (PMID: 9242490, 18485326). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with spondylocostal dysostosis (PMID: 18485326). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5184). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at