NM_001039958.2:c.558G>A

Variant names:

• chr15-89776915-G-A
• rs28546919
• NM_001039958.2:c.558G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001039958.2(MESP2):​c.558G>A​(p.Gln186Gln) 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 (★★).

• 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:5
• Conservation: PhyloP100: -3.36
• Publications: 8 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 257243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.36 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039958.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MESP2	NM_001039958.2	MANE Select	c.558G>A	p.Gln186Gln	synonymous	Exon 1 of 2	NP_001035047.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MESP2	ENST00000341735.5	TSL:1 MANE Select	c.558G>A	p.Gln186Gln	synonymous	Exon 1 of 2	ENSP00000342392.3
	MESP2	ENST00000560219.2	TSL:1	c.31-1150G>A		intron	N/A	ENSP00000452998.1
	MESP2	ENST00000558723.1	TSL:3	n.39-1150G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.469 AC: 7540 AN: 16080 Hom.: 617 Cov.: 0

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

GnomAD2 exomes AF: 0.0253 AC: 1540 AN: 60828 AF XY: 0.0237

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 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

African (AFR) AF: 0.520 AC: 5081 AN: 9766

American (AMR) AF: 0.226 AC: 295 AN: 1306

Ashkenazi Jewish (ASJ) AF: 0.00815 AC: 3 AN: 368

East Asian (EAS) AF: 0.00219 AC: 7 AN: 3194

South Asian (SAS) AF: 0.422 AC: 1888 AN: 4476

European-Finnish (FIN) AF: 0.00345 AC: 5 AN: 1448

Middle Eastern (MID) AF: 0.400 AC: 76 AN: 190

European-Non Finnish (NFE) AF: 0.0259 AC: 709 AN: 27354

Other (OTH) AF: 0.276 AC: 767 AN: 2784

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

African (AFR) AF: 0.495 AC: 7044 AN: 14244

American (AMR) AF: 0.379 AC: 240 AN: 634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26

East Asian (EAS) AF: 0.00 AC: 0 AN: 44

South Asian (SAS) AF: 0.447 AC: 136 AN: 304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 74

Middle Eastern (MID) AF: 0.400 AC: 8 AN: 20

European-Non Finnish (NFE) AF: 0.106 AC: 66 AN: 624

Other (OTH) AF: 0.431 AC: 56 AN: 130

Alfa AF: 0.503 Hom.: 74

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Spondylocostal dysostosis 2, autosomal recessive (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.44
PhyloP100		-3.4
Mutation Taster		=100/0	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: rs28546919; hg19: chr15-90320146; COSMIC: COSV59091975;