15-89776598-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001039958.2(MESP2):​c.241G>T​(p.Gly81*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000918 in 1,524,286 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000095 ( 0 hom. )

Consequence

MESP2
NM_001039958.2 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.35
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-89776598-G-T is Pathogenic according to our data. Variant chr15-89776598-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MESP2NM_001039958.2 linkc.241G>T p.Gly81* stop_gained 1/2 ENST00000341735.5 NP_001035047.1 Q0VG99
LOC124903550XR_007064751.1 linkn.12C>A non_coding_transcript_exon_variant 1/2
LOC124903550XR_007064752.1 linkn.-24C>A upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MESP2ENST00000341735.5 linkc.241G>T p.Gly81* stop_gained 1/21 NM_001039958.2 ENSP00000342392.3 Q0VG99
MESP2ENST00000560219.2 linkc.31-1467G>T intron_variant 1 ENSP00000452998.1 H0YKZ5
MESP2ENST00000558723.1 linkn.39-1467G>T intron_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152260
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000253
AC:
3
AN:
118804
Hom.:
0
AF XY:
0.0000151
AC XY:
1
AN XY:
66398
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000117
Gnomad SAS exome
AF:
0.0000479
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000219
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000948
AC:
13
AN:
1372026
Hom.:
0
Cov.:
31
AF XY:
0.00000738
AC XY:
5
AN XY:
677204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000296
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000931
Gnomad4 OTH exome
AF:
0.0000349
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152260
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000196
AC:
2

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Spondylocostal dysostosis 2, autosomal recessive Pathogenic:2
Pathogenic, no assertion criteria providedcurationGeneReviewsAug 05, 2010- -
Likely pathogenic, criteria provided, single submitterclinical testingCounsylAug 30, 2017- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 15, 2023For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 38907). This variant has not been reported in the literature in individuals affected with MESP2-related conditions. 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 sequence change creates a premature translational stop signal (p.Gly81*) 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). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
35
DANN
Uncertain
0.98
Eigen
Benign
0.18
Eigen_PC
Benign
-0.17
FATHMM_MKL
Benign
0.20
N
Vest4
0.24
GERP RS
2.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs118204034; hg19: chr15-90319829; API