rs113097169

Variant names:

• chr15-89776930-G-A
• rs113097169
• NM_001039958.2:c.573G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-89776930-G-A
• chr15-89776930-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001039958.2(MESP2):​c.573G>A​(p.Gly191Gly) 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G191G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (16 hom., cov: 0)
  • Exomes 𝑓: 0.10 (85 hom.)
  • Failed GnomAD Quality Control
• Consequence: MESP2 NM_001039958.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -1.11
• Publications: 9 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 15-89776930-G-A is Benign according to our data. Variant chr15-89776930-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 317389.
• BP7: Synonymous conserved (PhyloP=-1.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MESP2	NM_001039958.2	MANE Select	c.573G>A	p.Gly191Gly	synonymous	Exon 1 of 2	NP_001035047.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MESP2	ENST00000341735.5	TSL:1 MANE Select	c.573G>A	p.Gly191Gly	synonymous	Exon 1 of 2	ENSP00000342392.3
	MESP2	ENST00000560219.2	TSL:1	c.31-1135G>A		intron	N/A	ENSP00000452998.1
	MESP2	ENST00000558723.1	TSL:3	n.39-1135G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.132 AC: 1502 AN: 11408 Hom.: 16 Cov.: 0

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.450

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0769

Gnomad EAS AF: 0.00735

Gnomad SAS AF: 0.0327

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.00846 AC: 424 AN: 50138 AF XY: 0.00772

Gnomad AFR exome AF: 0.00184

Gnomad AMR exome AF: 0.00796

Gnomad ASJ exome AF: 0.00125

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0264

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0126

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.102 AC: 14434 AN: 141128 Hom.: 85 Cov.: 0 AF XY: 0.0983 AC XY: 6922 AN XY: 70444

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0102 AC: 70 AN: 6854

American (AMR) AF: 0.0197 AC: 124 AN: 6292

Ashkenazi Jewish (ASJ) AF: 0.00751 AC: 21 AN: 2798

East Asian (EAS) AF: 0.000912 AC: 6 AN: 6576

South Asian (SAS) AF: 0.0116 AC: 106 AN: 9174

European-Finnish (FIN) AF: 0.125 AC: 803 AN: 6440

Middle Eastern (MID) AF: 0.0137 AC: 6 AN: 438

European-Non Finnish (NFE) AF: 0.134 AC: 12820 AN: 95802

Other (OTH) AF: 0.0708 AC: 478 AN: 6754

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.132 AC: 1502 AN: 11416 Hom.: 16 Cov.: 0 AF XY: 0.140 AC XY: 790 AN XY: 5636

African (AFR) AF: 0.0224 AC: 141 AN: 6288

American (AMR) AF: 0.124 AC: 95 AN: 766

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 4 AN: 52

East Asian (EAS) AF: 0.00735 AC: 1 AN: 136

South Asian (SAS) AF: 0.0330 AC: 7 AN: 212

European-Finnish (FIN) AF: 0.352 AC: 315 AN: 894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.310 AC: 890 AN: 2874

Other (OTH) AF: 0.120 AC: 13 AN: 108

Alfa AF: 0.277 Hom.: 2

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Spondylocostal dysostosis 2, autosomal recessive (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.2
DANN	Benign	0.48
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

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: rs113097169; hg19: chr15-90320161; COSMIC: COSV59092119;