rs28546919

Positions:

• chr15-89776915-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001039958.2(MESP2):​c.558G>A​(p.Gln186=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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. QGQGQG186QG) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.47 (617 hom., cov: 0)
  • Exomes 𝑓: 0.17 (677 hom.)
  • Failed GnomAD Quality Control
• Consequence: MESP2 NM_001039958.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.36

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-89776915-G-A is Benign according to our data. Variant chr15-89776915-G-A is described in ClinVar as [Benign]. Clinvar id is 257243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89776915-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.36 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MESP2	NM_001039958.2	c.558G>A	p.Gln186=	synonymous_variant	1/2	ENST00000341735.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MESP2	ENST00000341735.5	c.558G>A	p.Gln186=	synonymous_variant	1/2	1	NM_001039958.2	P1
MESP2	ENST00000560219.2	c.31-1150G>A		intron_variant		1
MESP2	ENST00000558723.1	n.39-1150G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 7540 AN: 16080 Hom.: 617 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.400

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.431

GnomAD3 exomes AF: 0.0253 AC: 1540 AN: 60828 Hom.: 234 AF XY: 0.0237 AC XY: 787 AN XY: 33208

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.000980

Gnomad EAS exome AF: 0.00295

Gnomad SAS exome AF: 0.0375

Gnomad FIN exome AF: 0.00250

Gnomad NFE exome AF: 0.00310

Gnomad OTH exome AF: 0.0100

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.174 AC: 8831 AN: 50886 Hom.: 677 Cov.: 0 AF XY: 0.179 AC XY: 4454 AN XY: 24926

Gnomad4 AFR exome AF: 0.520

Gnomad4 AMR exome AF: 0.226

Gnomad4 ASJ exome AF: 0.00815

Gnomad4 EAS exome AF: 0.00219

Gnomad4 SAS exome AF: 0.422

Gnomad4 FIN exome AF: 0.00345

Gnomad4 NFE exome AF: 0.0259

Gnomad4 OTH exome AF: 0.276

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.469 AC: 7550 AN: 16108 Hom.: 617 Cov.: 0 AF XY: 0.469 AC XY: 3596 AN XY: 7668

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.447

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.431

Alfa AF: 0.503 Hom.: 74

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylocostal dysostosis 2, autosomal recessive Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 26, 2019	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.44

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: rs28546919; hg19: chr15-90320146; COSMIC: COSV59091975;