rs75049807

Positions:

• chr15-89776888-G-A
• chr15-89776888-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001039958.2(MESP2):​c.531G>A​(p.Ala177=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0485 in 1,450,976 control chromosomes in the GnomAD database, including 1,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (141 hom., cov: 33)
  • Exomes 𝑓: 0.050 (1691 hom.)
• Consequence: MESP2 NM_001039958.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.182

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 15-89776888-G-A is Benign according to our data. Variant chr15-89776888-G-A is described in ClinVar as [Benign]. Clinvar id is 257241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.182 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MESP2	NM_001039958.2	c.531G>A	p.Ala177=	synonymous_variant	1/2	ENST00000341735.5	NP_001035047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MESP2	ENST00000341735.5	c.531G>A	p.Ala177=	synonymous_variant	1/2	1	NM_001039958.2	ENSP00000342392	P1
MESP2	ENST00000560219.2	c.31-1177G>A		intron_variant		1		ENSP00000452998
MESP2	ENST00000558723.1	n.39-1177G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5841 AN: 151638 Hom.: 139 Cov.: 33

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0327

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.0692

Gnomad SAS AF: 0.0358

Gnomad FIN AF: 0.0452

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0516

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0487 AC: 3706 AN: 76110 Hom.: 135 AF XY: 0.0491 AC XY: 2023 AN XY: 41178

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.0339

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.0796

Gnomad SAS exome AF: 0.0367

Gnomad FIN exome AF: 0.0610

Gnomad NFE exome AF: 0.0550

Gnomad OTH exome AF: 0.0406

GnomAD4 exome AF: 0.0496 AC: 64477 AN: 1299226 Hom.: 1691 Cov.: 31 AF XY: 0.0497 AC XY: 31487 AN XY: 632938

Gnomad4 AFR exome AF: 0.0172

Gnomad4 AMR exome AF: 0.0365

Gnomad4 ASJ exome AF: 0.0120

Gnomad4 EAS exome AF: 0.0645

Gnomad4 SAS exome AF: 0.0359

Gnomad4 FIN exome AF: 0.0522

Gnomad4 NFE exome AF: 0.0523

Gnomad4 OTH exome AF: 0.0415

GnomAD4 genome AF: 0.0386 AC: 5851 AN: 151750 Hom.: 141 Cov.: 33 AF XY: 0.0378 AC XY: 2803 AN XY: 74116

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.0327

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.0694

Gnomad4 SAS AF: 0.0357

Gnomad4 FIN AF: 0.0452

Gnomad4 NFE AF: 0.0516

Gnomad4 OTH AF: 0.0355

Alfa AF: 0.00345 Hom.: 3

Bravo AF: 0.0363

Asia WGS AF: 0.0580 AC: 200 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Spondylocostal dysostosis 2, autosomal recessive Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.6
DANN	Benign	0.75

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: rs75049807; hg19: chr15-90320119; COSMIC: COSV59092036;