rs113097169
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1
The NM_001039958.2(MESP2):c.573G>A(p.Gly191=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G191G) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.13 ( 16 hom., cov: 0)
Exomes 𝑓: 0.10 ( 85 hom. )
Failed GnomAD Quality Control
Consequence
MESP2
NM_001039958.2 synonymous
NM_001039958.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.11
Genes affected
MESP2 (HGNC:29659): (mesoderm posterior bHLH transcription factor 2) This gene encodes a member of the bHLH family of transcription factors and plays a key role in defining the rostrocaudal patterning of somites via interactions with multiple Notch signaling pathways. This gene is expressed in the anterior presomitic mesoderm and is downregulated immediately after the formation of segmented somites. This gene also plays a role in the formation of epithelial somitic mesoderm and cardiac mesoderm. Mutations in the MESP2 gene cause autosomal recessive spondylocostal dystosis 2 (SCD02). [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
?
Variant 15-89776930-G-A is Benign according to our data. Variant chr15-89776930-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 317389.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.
BP7
?
Synonymous conserved (PhyloP=-1.11 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MESP2 | NM_001039958.2 | c.573G>A | p.Gly191= | synonymous_variant | 1/2 | ENST00000341735.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MESP2 | ENST00000341735.5 | c.573G>A | p.Gly191= | synonymous_variant | 1/2 | 1 | NM_001039958.2 | P1 | |
MESP2 | ENST00000560219.2 | c.31-1135G>A | intron_variant | 1 | |||||
MESP2 | ENST00000558723.1 | n.39-1135G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.132 AC: 1502AN: 11408Hom.: 16 Cov.: 0
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GnomAD3 exomes AF: 0.00846 AC: 424AN: 50138Hom.: 0 AF XY: 0.00772 AC XY: 215AN XY: 27850
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.102 AC: 14434AN: 141128Hom.: 85 Cov.: 0 AF XY: 0.0983 AC XY: 6922AN XY: 70444
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GnomAD4 genome ? AF: 0.132 AC: 1502AN: 11416Hom.: 16 Cov.: 0 AF XY: 0.140 AC XY: 790AN XY: 5636
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Spondylocostal dysostosis 2, autosomal recessive Uncertain:2Benign:1
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 18, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 10, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent variant not near splice site - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2023 | Variant summary: MESP2 c.573G>A results in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0085 in 50138 control chromosomes. The observed variant frequency is approximately 7.56 fold of the estimated maximal expected allele frequency for a pathogenic variant in MESP2 causing Spondylocostal Dysostosis 2 phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.573G>A in individuals affected with Spondylocostal Dysostosis 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at