rs28462216

chr15-89776769-G-Achr15-89776769-G-Cchr15-89776769-G-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.412G>A(p.Val138Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,531,108 control chromosomes in the GnomAD database, including 1,678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V138V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.061 (900 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (778 hom.)
• Consequence: MESP2 NM_001039958.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.612

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=0.0016154945).
• BP6: Variant 15-89776769-G-A is Benign according to our data. Variant chr15-89776769-G-A is described in ClinVar as [Benign]. Clinvar id is 257239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MESP2	NM_001039958.2	c.412G>A	p.Val138Met	missense_variant	1/2	ENST00000341735.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MESP2	ENST00000341735.5	c.412G>A	p.Val138Met	missense_variant	1/2	1	NM_001039958.2	P1
MESP2	ENST00000560219.2	c.31-1296G>A		intron_variant		1
MESP2	ENST00000558723.1	n.39-1296G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0610 AC: 9282 AN: 152228 Hom.: 901 Cov.: 33

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.0377

GnomAD3 exomes AF: 0.0147 AC: 2266 AN: 154542 Hom.: 159 AF XY: 0.0131 AC XY: 1132 AN XY: 86644

Gnomad AFR exome AF: 0.202

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000331

Gnomad SAS exome AF: 0.0272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000623

Gnomad OTH exome AF: 0.00723

GnomAD4 exome AF: 0.00734 AC: 10124 AN: 1378770 Hom.: 778 Cov.: 30 AF XY: 0.00737 AC XY: 5020 AN XY: 681270

Gnomad4 AFR exome AF: 0.217

Gnomad4 AMR exome AF: 0.0122

Gnomad4 ASJ exome AF: 0.0000922

Gnomad4 EAS exome AF: 0.000197

Gnomad4 SAS exome AF: 0.0280

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000467

Gnomad4 OTH exome AF: 0.0164

GnomAD4 genome AF: 0.0610 AC: 9296 AN: 152338 Hom.: 900 Cov.: 33 AF XY: 0.0592 AC XY: 4408 AN XY: 74484

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.0373

Alfa AF: 0.0202 Hom.: 63

Bravo AF: 0.0691

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.185 AC: 771

ESP6500EA AF: 0.000598 AC: 5

ExAC AF: 0.0191 AC: 2281

Asia WGS AF: 0.0270 AC: 94 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylocostal dysostosis 2, autosomal recessive Benign:2

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 27, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.0014
Eigen_PC	Benign	-0.093
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.014	D
Sift4G	Benign	0.067	T
Polyphen		0.99	D
Vest4		0.094
MPC		0.66
ClinPred		0.026	T
GERP RS		1.8
Varity_R		0.060
gMVP		0.21

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: rs28462216; hg19: chr15-90320000;