chr15-89776554-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001039958.2(MESP2):c.197C>G(p.Ala66Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 1,532,208 control chromosomes in the GnomAD database, including 391 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A66T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.029 ( 213 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 178 hom. )

Consequence

MESP2
NM_001039958.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.23

Publications

4 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:

LOC124903550 (HGNC:):

LOC124903550 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017988086).

BP6

Variant 15-89776554-C-G is Benign according to our data. Variant chr15-89776554-C-G is described in ClinVar as Benign. ClinVar VariationId is 38906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MESP2	NM_001039958.2 link	c.197C>G	p.Ala66Gly	missense_variant	Exon 1 of 2	ENST00000341735.5	NP_001035047.1	Q0VG99
LOC124903550	XR_007064751.1 link	n.56G>C		non_coding_transcript_exon_variant	Exon 1 of 2
LOC124903550	XR_007064752.1 link	n.21G>C		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MESP2	ENST00000341735.5 link	c.197C>G	p.Ala66Gly	missense_variant	Exon 1 of 2	1	NM_001039958.2	ENSP00000342392.3	Q0VG99
MESP2	ENST00000560219.2 link	c.31-1511C>G		intron_variant	Intron 2 of 2	1		ENSP00000452998.1	H0YKZ5
MESP2	ENST00000558723.1 link	n.39-1511C>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.0285

AC:

4339

AN:

152260

Hom.:

213

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0981

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.0196

GnomAD2 exomes

AF:

0.00576

AC:

727

AN:

126298

AF XY:

0.00439

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.00587

Gnomad ASJ exome

AF:

0.000762

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000746

Gnomad OTH exome

AF:

0.00256

GnomAD4 exome

AF:

0.00315

AC:

4340

AN:

1379832

Hom.:

178

Cov.:

AF XY:

0.00273

AC XY:

1859

AN XY:

680776

show subpopulations

African (AFR)

AF:

0.106

AC:

3234

AN:

30642

American (AMR)

AF:

0.00628

AC:

223

AN:

35532

Ashkenazi Jewish (ASJ)

AF:

0.000681

AC:

AN:

24956

East Asian (EAS)

AF:

0.00

AC:

AN:

35192

South Asian (SAS)

AF:

0.000241

AC:

AN:

78690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34988

Middle Eastern (MID)

AF:

0.00561

AC:

AN:

5170

European-Non Finnish (NFE)

AF:

0.000345

AC:

372

AN:

1077048

Other (OTH)

AF:

0.00774

AC:

446

AN:

57614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

270

540

810

1080

1350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.0285

AC:

4346

AN:

152376

Hom.:

213

Cov.:

AF XY:

0.0270

AC XY:

2010

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.0980

AC:

4075

AN:

41586

American (AMR)

AF:

0.0120

AC:

184

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000617

AC:

AN:

68034

Other (OTH)

AF:

0.0194

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

203

406

608

811

1014

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.00176

Hom.:

Bravo

AF:

0.0337

ESP6500AA

AF:

0.0684

AC:

175

ESP6500EA

AF:

0.000891

AC:

ExAC

AF:

0.00318

AC:

272

Asia WGS

AF:

0.00405

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spondylocostal dysostosis 2, autosomal recessive

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 05, 2010

GeneReviews

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.091

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

3.2

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.64

REVEL

Benign

0.12

Sift

Benign

0.068

Sift4G

Benign

0.13

Polyphen

0.0010

Vest4

0.15

MVP

0.50

MPC

0.82

ClinPred

0.024

GERP RS

0.21

PromoterAI

-0.060

Neutral

(source)

Varity_R

0.069

gMVP

0.26

Mutation Taster

=99/1

polymorphism (auto)

(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