rs113097169

Positions:

• chr15-89776930-G-A
• chr15-89776930-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• 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]

ACMG classification

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: 1502 AN: 11408 Hom.: 16 Cov.: 0

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.450

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0769

Gnomad EAS AF: 0.00735

Gnomad SAS AF: 0.0327

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.00846 AC: 424 AN: 50138 Hom.: 0 AF XY: 0.00772 AC XY: 215 AN XY: 27850

Gnomad AFR exome AF: 0.00184

Gnomad AMR exome AF: 0.00796

Gnomad ASJ exome AF: 0.00125

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00240

Gnomad FIN exome AF: 0.0264

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0126

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.102 AC: 14434 AN: 141128 Hom.: 85 Cov.: 0 AF XY: 0.0983 AC XY: 6922 AN XY: 70444

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.0197

Gnomad4 ASJ exome AF: 0.00751

Gnomad4 EAS exome AF: 0.000912

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.0708

GnomAD4 genome AF: 0.132 AC: 1502 AN: 11416 Hom.: 16 Cov.: 0 AF XY: 0.140 AC XY: 790 AN XY: 5636

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.0769

Gnomad4 EAS AF: 0.00735

Gnomad4 SAS AF: 0.0330

Gnomad4 FIN AF: 0.352

Gnomad4 NFE AF: 0.310

Gnomad4 OTH AF: 0.120

Alfa AF: 0.277 Hom.: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spondylocostal dysostosis 2, autosomal recessive Uncertain:2 Benign: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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.2
DANN	Benign	0.48

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: rs113097169; hg19: chr15-90320161; COSMIC: COSV59092119;