rs71647807

chr15-89777028-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.77

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 -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 id 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/exons	MANE	UniProt
MESP2	NM_001039958.2	c.671C>T	p.Ser224Phe	missense_variant	1/2	ENST00000341735.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MESP2	ENST00000341735.5	c.671C>T	p.Ser224Phe	missense_variant	1/2	1	NM_001039958.2	P1
MESP2	ENST00000560219.2	c.31-1037C>T		intron_variant		1
MESP2	ENST00000558723.1	n.39-1037C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3627 AN: 152186 Hom.: 157 Cov.: 32

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

GnomAD3 exomes AF: 0.00524 AC: 1071 AN: 204502 Hom.: 37 AF XY: 0.00392 AC XY: 445 AN XY: 113540

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 SAS exome AF: 0.000145

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.: 34 AF XY: 0.00196 AC XY: 1401 AN XY: 715540

Gnomad4 AFR exome AF: 0.0834

Gnomad4 AMR exome AF: 0.00549

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000227

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000553

Gnomad4 OTH exome AF: 0.00561

GnomAD4 genome AF: 0.0240 AC: 3649 AN: 152302 Hom.: 160 Cov.: 32 AF XY: 0.0234 AC XY: 1739 AN XY: 74470

Gnomad4 AFR AF: 0.0834

Gnomad4 AMR AF: 0.00823

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00706 Hom.: 7

Bravo AF: 0.0282

ESP6500AA AF: 0.0718 AC: 262

ESP6500EA AF: 0.000125 AC: 1

ExAC AF: 0.00601 AC: 714

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylocostal dysostosis 2, autosomal recessive Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jan 09, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.99	D;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.91	P
Vest4		0.20
MVP		0.75
MPC		0.81
ClinPred		0.050	T
GERP RS		3.5
Varity_R		0.099
gMVP		0.15

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: rs71647807; hg19: chr15-90320259;