rs185706635

chr15-89777265-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001039958.2(MESP2):c.908T>C(p.Leu303Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,611,070 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L303V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (50 hom.)
• Consequence: MESP2 NM_001039958.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.683

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041748583).
• BP6: Variant 15-89777265-T-C is Benign according to our data. Variant chr15-89777265-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89777265-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00189 (288/152368) while in subpopulation EAS AF= 0.0289 (150/5188). AF 95% confidence interval is 0.0251. There are 4 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MESP2	NM_001039958.2	c.908T>C	p.Leu303Pro	missense_variant	1/2	ENST00000341735.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MESP2	ENST00000341735.5	c.908T>C	p.Leu303Pro	missense_variant	1/2	1	NM_001039958.2	P1
MESP2	ENST00000560219.2	c.31-800T>C		intron_variant		1
MESP2	ENST00000558723.1	n.39-800T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 288 AN: 152250 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0288

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00470 AC: 1123 AN: 239054 Hom.: 23 AF XY: 0.00400 AC XY: 526 AN XY: 131586

Gnomad AFR exome AF: 0.000144

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.0296

Gnomad SAS exome AF: 0.000233

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000653

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00155 AC: 2258 AN: 1458702 Hom.: 50 Cov.: 34 AF XY: 0.00141 AC XY: 1023 AN XY: 725436

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0151

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0357

Gnomad4 SAS exome AF: 0.000268

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00189 AC: 288 AN: 152368 Hom.: 4 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74516

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00816

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0289

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00146 Hom.: 4

Bravo AF: 0.00265

ExAC AF: 0.00414 AC: 498

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylocostal dysostosis 2, autosomal recessive Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

MESP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.33	B
Vest4		0.45
MVP		0.73
MPC		1.8
ClinPred		0.027	T
GERP RS		3.5
Varity_R		0.51
gMVP		0.43

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: rs185706635; hg19: chr15-90320496; COSMIC: COSV59093402;