rs113097169

Positions:

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.Gly191Gly) 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).

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -1.11

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]

MESP2 links:

Genome browser will be placed here

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: {Uncertain_significance=2, Likely_benign=1, 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	Protein	UniProt
MESP2	NM_001039958.2 link	c.573G>A	p.Gly191Gly	synonymous_variant	1/2	ENST00000341735.5	NP_001035047.1	Q0VG99

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MESP2	ENST00000341735.5 link	c.573G>A	p.Gly191Gly	synonymous_variant	1/2	1	NM_001039958.2	ENSP00000342392.3	Q0VG99
MESP2	ENST00000560219.2 link	c.31-1135G>A		intron_variant		1		ENSP00000452998.1	H0YKZ5
MESP2	ENST00000558723.1 link	n.39-1135G>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

1502

AN:

11408

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00772

AC XY:

215

AN XY:

27850

show subpopulations

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.:

Cov.:

AF XY:

0.0983

AC XY:

6922

AN XY:

70444

show subpopulations

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.:

Cov.:

AF XY:

0.140

AC XY:

790

AN XY:

5636

show subpopulations

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.:

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

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. -
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	- -

not specified

Benign:2

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. -
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 -

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over