NM_001039958.2:c.412G>A

Variant names:

• chr15-89776769-G-A
• rs28462216
• NM_001039958.2:c.412G>A

Variant summary

Our verdict is Benign. The variant received -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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V138L) has been classified as Uncertain significance.

• 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:6
• Conservation: PhyloP100: 0.612
• Publications: 5 publications found

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

LOC124903550 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MESP2	NM_001039958.2	c.412G>A	p.Val138Met	missense_variant	Exon 1 of 2	ENST00000341735.5	NP_001035047.1
LOC124903550	XR_007064751.1	n.-160C>T		upstream_gene_variant
LOC124903550	XR_007064752.1	n.-195C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MESP2	ENST00000341735.5	c.412G>A	p.Val138Met	missense_variant	Exon 1 of 2	1	NM_001039958.2	ENSP00000342392.3
MESP2	ENST00000560219.2	c.31-1296G>A		intron_variant	Intron 2 of 2	1		ENSP00000452998.1
MESP2	ENST00000558723.1	n.39-1296G>A		intron_variant	Intron 1 of 1	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

GnomAD2 exomes AF: 0.0147 AC: 2266 AN: 154542 AF XY: 0.0131

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 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

African (AFR) AF: 0.217 AC: 6080 AN: 27964

American (AMR) AF: 0.0122 AC: 409 AN: 33530

Ashkenazi Jewish (ASJ) AF: 0.0000922 AC: 2 AN: 21698

East Asian (EAS) AF: 0.000197 AC: 7 AN: 35490

South Asian (SAS) AF: 0.0280 AC: 2095 AN: 74762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45750

Middle Eastern (MID) AF: 0.0183 AC: 99 AN: 5398

European-Non Finnish (NFE) AF: 0.000467 AC: 503 AN: 1077442

Other (OTH) AF: 0.0164 AC: 929 AN: 56736

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

African (AFR) AF: 0.209 AC: 8694 AN: 41562

American (AMR) AF: 0.0201 AC: 307 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0292 AC: 141 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68024

Other (OTH) AF: 0.0373 AC: 79 AN: 2116

Alfa AF: 0.0245 Hom.: 133

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 09, 2021

GeneDx

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spondylocostal dysostosis 2, autosomal recessive Benign:2

Nov 27, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 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	0.26
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
PhyloP100		0.61
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
PromoterAI		0.27	Neutral
Varity_R		0.060
gMVP		0.21
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28462216; hg19: chr15-90320000;