5-174724786-T-C

Position:

• chr5-174724786-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002449.5(MSX2):​c.127T>C​(p.Ser43Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MSX2 NM_002449.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19

Genes affected

MSX2 (HGNC:7392): (msh homeobox 2) This gene encodes a member of the muscle segment homeobox gene family. The encoded protein is a transcriptional repressor whose normal activity may establish a balance between survival and apoptosis of neural crest-derived cells required for proper craniofacial morphogenesis. The encoded protein may also have a role in promoting cell growth under certain conditions and may be an important target for the RAS signaling pathways. Mutations in this gene are associated with parietal foramina 1 and craniosynostosis type 2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32381803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSX2	NM_002449.5	c.127T>C	p.Ser43Pro	missense_variant	1/2	ENST00000239243.7	NP_002440.2
MSX2	NM_001363626.2	c.127T>C	p.Ser43Pro	missense_variant	1/2		NP_001350555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSX2	ENST00000239243.7	c.127T>C	p.Ser43Pro	missense_variant	1/2	1	NM_002449.5	ENSP00000239243.5
MSX2	ENST00000507785.2	c.127T>C	p.Ser43Pro	missense_variant	1/2	2		ENSP00000427425.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402976 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 692606

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cranium bifidum occultum Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 18, 2023

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 43 of the MSX2 protein (p.Ser43Pro). This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSX2 protein function. This variant has not been reported in the literature in individuals affected with MSX2-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.018
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Uncertain	0.049	D
MutationAssessor	Benign	1.7	L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.4	N;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.020	D;D
Sift4G	Benign	0.21	T;T
Polyphen		0.0060	B;.
Vest4		0.22
MutPred		0.20		Loss of phosphorylation at S43 (P = 0.0281);Loss of phosphorylation at S43 (P = 0.0281);
MVP		0.95
MPC		1.1
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.63
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-174151789;