rs104893895

Variant names:

• chr5-174729222-C-A
• rs104893895
• NM_002449.5:c.443C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-174729222-C-A
• chr5-174729222-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. 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. P148S) has been classified as Uncertain significance.

• 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
• Publications: 19 publications found

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]

MSX2 Gene-Disease associations (from GenCC):

• craniosynostosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• parietal foramina

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• parietal foramina with cleidocranial dysplasia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• parietal foramina 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• 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 VariationId 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 VariationId is 16961.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSX2	NM_002449.5	c.443C>A	p.Pro148His	missense_variant	Exon 2 of 2	ENST00000239243.7	NP_002440.2
MSX2	NM_001363626.2	c.*67C>A		3_prime_UTR_variant	Exon 2 of 2		NP_001350555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSX2	ENST00000239243.7	c.443C>A	p.Pro148His	missense_variant	Exon 2 of 2	1	NM_002449.5	ENSP00000239243.5
MSX2	ENST00000507785.2	c.*67C>A		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000427425.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Craniosynostosis 2 Pathogenic:1 Other:1

Dec 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Cranium bifidum occultum Pathogenic:1

Sep 11, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). 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 has been reported to affect MSX2 protein function (PMID: 9256341, 27013732, 18786927). 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. For these reasons, this variant has been classified as Pathogenic. -

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
PhyloP100		7.9
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
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893895; hg19: chr5-174156225;