5-174724732-G-C

Position:

• chr5-174724732-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002449.5(MSX2):​c.73G>C​(p.Gly25Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSX2 NM_002449.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.09

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSX2	NM_002449.5	c.73G>C	p.Gly25Arg	missense_variant	1/2	ENST00000239243.7
MSX2	NM_001363626.2	c.73G>C	p.Gly25Arg	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSX2	ENST00000239243.7	c.73G>C	p.Gly25Arg	missense_variant	1/2	1	NM_002449.5	P1
MSX2	ENST00000507785.2	c.73G>C	p.Gly25Arg	missense_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000852 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.73G>C (p.G25R) alteration is located in exon 1 (coding exon 1) of the MSX2 gene. This alteration results from a G to C substitution at nucleotide position 73, causing the glycine (G) at amino acid position 25 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cranium bifidum occultum Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 10, 2023

ClinVar contains an entry for this variant (Variation ID: 1978706). This variant has not been reported in the literature in individuals affected with MSX2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 25 of the MSX2 protein (p.Gly25Arg). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.044
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.96	N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.025	D;D
Sift4G	Benign	0.43	T;T
Polyphen		0.26	B;.
Vest4		0.61
MutPred		0.33		Gain of methylation at G25 (P = 0.0183);Gain of methylation at G25 (P = 0.0183);
MVP		0.99
MPC		0.50
ClinPred		0.19	T
GERP RS		4.4
Varity_R		0.095
gMVP		0.57

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: rs778800326; hg19: chr5-174151735;