rs113097169

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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). 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

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.11

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

spondylocostal dysostosis 2, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal recessive spondylocostal dysostosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MESP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 317389.

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 rank	MANE	Protein	UniProt
MESP2	NM_001039958.2 link	c.573G>A	p.Gly191Gly	synonymous_variant	Exon 1 of 2	ENST00000341735.5	NP_001035047.1	Q0VG99

Ensembl

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

GnomAD2 exomes

AF:

0.00846

AC:

424

AN:

50138

AF XY:

0.00772

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0102

AC:

AN:

6854

American (AMR)

AF:

0.0197

AC:

124

AN:

6292

Ashkenazi Jewish (ASJ)

AF:

0.00751

AC:

AN:

2798

East Asian (EAS)

AF:

0.000912

AC:

AN:

6576

South Asian (SAS)

AF:

0.0116

AC:

106

AN:

9174

European-Finnish (FIN)

AF:

0.125

AC:

803

AN:

6440

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

438

European-Non Finnish (NFE)

AF:

0.134

AC:

12820

AN:

95802

Other (OTH)

AF:

0.0708

AC:

478

AN:

6754

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.377

Heterozygous variant carriers

570

1140

1710

2280

2850

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

486

972

1458

1944

2430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.132

AC:

1502

AN:

11416

Hom.:

Cov.:

AF XY:

0.140

AC XY:

790

AN XY:

5636

show subpopulations

African (AFR)

AF:

0.0224

AC:

141

AN:

6288

American (AMR)

AF:

0.124

AC:

AN:

766

Ashkenazi Jewish (ASJ)

AF:

0.0769

AC:

AN:

East Asian (EAS)

AF:

0.00735

AC:

AN:

136

South Asian (SAS)

AF:

0.0330

AC:

AN:

212

European-Finnish (FIN)

AF:

0.352

AC:

315

AN:

894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.310

AC:

890

AN:

2874

Other (OTH)

AF:

0.120

AC:

AN:

108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

135

203

270

338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jun 10, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 18, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 14, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.48

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over