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

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000032 ( 1 hom. )

Consequence

MESP2
ENST00000341735.5 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -0.370
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 15-89776664-G-T is Pathogenic according to our data. Variant chr15-89776664-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 5184.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 linkuse as main transcriptc.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
MESP2ENST00000341735.5 linkuse as main transcriptc.307G>T p.Glu103Ter stop_gained 1/21 NM_001039958.2 ENSP00000342392 P1
MESP2ENST00000560219.2 linkuse as main transcriptc.31-1401G>T intron_variant 1 ENSP00000452998
MESP2ENST00000558723.1 linkuse as main transcriptn.39-1401G>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152256
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00137
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000411
AC:
6
AN:
146096
Hom.:
0
AF XY:
0.0000243
AC XY:
2
AN XY:
82306
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000828
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00105
GnomAD4 exome
AF:
0.0000325
AC:
45
AN:
1386042
Hom.:
1
Cov.:
30
AF XY:
0.0000233
AC XY:
16
AN XY:
686038
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000564
Gnomad4 ASJ exome
AF:
0.0000421
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000111
Gnomad4 OTH exome
AF:
0.000209
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152368
Hom.:
0
Cov.:
33
AF XY:
0.000201
AC XY:
15
AN XY:
74508
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00137
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Bravo
AF:
0.000366

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Spondylocostal dysostosis 2, autosomal recessive Pathogenic:3
Pathogenic, no assertion criteria providedcurationGeneReviewsAug 05, 2010- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 01, 2008- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 12, 2018The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
36
DANN
Uncertain
0.99
Eigen
Benign
0.17
Eigen_PC
Benign
-0.18
FATHMM_MKL
Benign
0.37
N
MutationTaster
Benign
1.0
A;A
Vest4
0.52
GERP RS
1.6

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: rs71647808; hg19: chr15-90319895; API