15-89776368-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001039958.2(MESP2):c.11C>A(p.Ser4Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MESP2 NM_001039958.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.62

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]

LOC124903550 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-89776368-C-A is Pathogenic according to our data. Variant chr15-89776368-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MESP2	NM_001039958.2	c.11C>A	p.Ser4Ter	stop_gained	1/2	ENST00000341735.5
LOC124903550	XR_007064751.1	n.242G>T		non_coding_transcript_exon_variant	1/2
LOC124903550	XR_007064752.1	n.207G>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MESP2	ENST00000341735.5	c.11C>A	p.Ser4Ter	stop_gained	1/2	1	NM_001039958.2	P1
MESP2	ENST00000560219.2	c.31-1697C>A		intron_variant		1
MESP2	ENST00000558723.1	n.39-1697C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1379746 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 681004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylocostal dysostosis 2, autosomal recessive Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2023	Variant summary: MESP2 c.11C>A (p.Ser4X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.116C>A [p.Ser39Ter], c.258_261del [p.Glu88fs]). The variant was absent in 126698 control chromosomes (gnomAD). To our knowledge, no occurrence of c.11C>A in individuals affected with Spondylocostal Dysostosis 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 08, 2017	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 12, 2023

ClinVar contains an entry for this variant (Variation ID: 554878). This variant has not been reported in the literature in individuals affected with MESP2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser4*) 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). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.014
FATHMM_MKL	Benign	0.46	N
MutationTaster	Benign	1.0	A;D
Vest4		0.49
GERP RS		3.7

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

Other links and lift over

dbSNP: rs1555439013; hg19: chr15-90319599;