5-174724703-A-G

Position:

• chr5-174724703-A-G

Variant summary

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

The NM_002449.5(MSX2):​c.44A>G​(p.Glu15Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,364 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E15K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: MSX2 NM_002449.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76

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=0.40584078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSX2	NM_002449.5	c.44A>G	p.Glu15Gly	missense_variant	1/2	ENST00000239243.7
MSX2	NM_001363626.2	c.44A>G	p.Glu15Gly	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSX2	ENST00000239243.7	c.44A>G	p.Glu15Gly	missense_variant	1/2	1	NM_002449.5	P1
MSX2	ENST00000507785.2	c.44A>G	p.Glu15Gly	missense_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398364 Hom.: 0 Cov.: 34 AF XY: 0.00000144 AC XY: 1 AN XY: 695526

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: 9.40e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Craniosynostosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 17, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene, the former is associated with parietal foramina 1 (MIM#168500), while the latter is associated with craniosynostosis 2 (MIM#604757) (PMIDs: 10742103, 8968743). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Craniosynostosis 2 (MIM#604757) has been reported to have intrafamilial phenotypic variability (PMID: 23949913). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.084	T;D
Polyphen		0.95	P;.
Vest4		0.31
MutPred		0.10		Gain of glycosylation at S12 (P = 0.0477);Gain of glycosylation at S12 (P = 0.0477);
MVP		0.96
MPC		0.52
ClinPred		0.88	D
GERP RS		4.4
Varity_R		0.19
gMVP		0.67

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: rs1760735851; hg19: chr5-174151706;