15-89777028-C-T

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.671C>T(p.Ser224Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00441 in 1,593,132 control chromosomes in the GnomAD database, including 282 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. S224P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.024 ( 160 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 122 hom. )

Consequence

MESP2
NM_001039958.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.77

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001771003).

BP6

Variant 15-89777028-C-T is Benign according to our data. Variant chr15-89777028-C-T is described in ClinVar as Benign. ClinVar VariationId is 257247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MESP2	NM_001039958.2 link	c.671C>T	p.Ser224Phe	missense_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.671C>T	p.Ser224Phe	missense_variant	Exon 1 of 2	1	NM_001039958.2	ENSP00000342392.3	Q0VG99
MESP2	ENST00000560219.2 link	c.31-1037C>T		intron_variant	Intron 2 of 2	1		ENSP00000452998.1	H0YKZ5
MESP2	ENST00000558723.1 link	n.39-1037C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.0238

AC:

3627

AN:

152186

Hom.:

157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0831

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00824

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0181

GnomAD2 exomes

AF:

0.00524

AC:

1071

AN:

204502

AF XY:

0.00392

show subpopulations

Gnomad AFR exome

AF:

0.0850

Gnomad AMR exome

AF:

0.00481

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.00153

GnomAD4 exome

AF:

0.00234

AC:

3374

AN:

1440830

Hom.:

122

Cov.:

AF XY:

0.00196

AC XY:

1401

AN XY:

715540

show subpopulations

African (AFR)

AF:

0.0834

AC:

2716

AN:

32550

American (AMR)

AF:

0.00549

AC:

231

AN:

42080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25780

East Asian (EAS)

AF:

0.00

AC:

AN:

37670

South Asian (SAS)

AF:

0.000227

AC:

AN:

83826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50288

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000553

AC:

AN:

1103364

Other (OTH)

AF:

0.00561

AC:

334

AN:

59520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

230

459

689

918

1148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.0240

AC:

3649

AN:

152302

Hom.:

160

Cov.:

AF XY:

0.0234

AC XY:

1739

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0834

AC:

3468

AN:

41566

American (AMR)

AF:

0.00823

AC:

126

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68018

Other (OTH)

AF:

0.0180

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

174

348

523

697

871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.00771

Hom.:

Bravo

AF:

0.0282

ESP6500AA

AF:

0.0718

AC:

262

ESP6500EA

AF:

0.000125

AC:

ExAC

AF:

0.00601

AC:

714

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spondylocostal dysostosis 2, autosomal recessive

Benign:3

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. -

Jan 09, 2018

Counsyl

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Nov 26, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Jun 10, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.13

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.16

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

1.8

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.9

REVEL

Benign

0.23

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.010

Polyphen

0.91

Vest4

0.20

MVP

0.75

MPC

0.81

ClinPred

0.050

GERP RS

3.5

Varity_R

0.099

gMVP

0.15

Mutation Taster

=92/8

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