rs104893895

chr5-174729222-C-Achr5-174729222-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_002449.5(MSX2):c.443C>A(p.Pro148His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P148L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSX2 NM_002449.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.86

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity MSX2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002449.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-174729222-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 219192.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 5-174729222-C-A is Pathogenic according to our data. Variant chr5-174729222-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 16961.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSX2	NM_002449.5	c.443C>A	p.Pro148His	missense_variant	2/2	ENST00000239243.7
MSX2	NM_001363626.2	c.*67C>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSX2	ENST00000239243.7	c.443C>A	p.Pro148His	missense_variant	2/2	1	NM_002449.5	P1
MSX2	ENST00000507785.2	c.*67C>A		3_prime_UTR_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Craniosynostosis 2 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1996	- -

Cranium bifidum occultum Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 11, 2019

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro148 amino acid residue in MSX2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23949913, 23918290). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect MSX2 protein function (PMID: 9256341, 27013732, 18786927). This variant has been observed to segregate with Boston-type craniosynostosis in a family (PMID: 8106171). ClinVar contains an entry for this variant (Variation ID: 16961). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with histidine at codon 148 of the MSX2 protein (p.Pro148His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.78		Loss of glycosylation at P148 (P = 0.0247);
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.73

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: rs104893895; hg19: chr5-174156225;