NM_002449.5:c.386T>C

Variant names:

• chr5-174729165-T-C
• rs4242182
• NM_002449.5:c.386T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002449.5(MSX2):​c.386T>C​(p.Met129Thr) variant causes a missense change. The variant allele was found at a frequency of 0.884 in 1,613,640 control chromosomes in the GnomAD database, including 638,388 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M129R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.78 (49255 hom., cov: 30)
  • Exomes 𝑓: 0.89 (589133 hom.)
• Consequence: MSX2 NM_002449.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.52
• Publications: 44 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.9376716E-7).
• BP6: Variant 5-174729165-T-C is Benign according to our data. Variant chr5-174729165-T-C is described in ClinVar as [Benign]. Clinvar id is 258657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSX2	NM_002449.5	c.386T>C	p.Met129Thr	missense_variant	Exon 2 of 2	ENST00000239243.7	NP_002440.2
MSX2	NM_001363626.2	c.*10T>C		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.386T>C	p.Met129Thr	missense_variant	Exon 2 of 2	1	NM_002449.5	ENSP00000239243.5
MSX2	ENST00000507785.2	c.*10T>C		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000427425.1

Frequencies

GnomAD3 genomes AF: 0.779 AC: 118356 AN: 151886 Hom.: 49247 Cov.: 30

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.874

Gnomad ASJ AF: 0.900

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.914

Gnomad FIN AF: 0.915

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.901

Gnomad OTH AF: 0.812

GnomAD2 exomes AF: 0.885 AC: 222305 AN: 251302 AF XY: 0.892

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.926

Gnomad ASJ exome AF: 0.906

Gnomad EAS exome AF: 0.983

Gnomad FIN exome AF: 0.915

Gnomad NFE exome AF: 0.902

Gnomad OTH exome AF: 0.890

GnomAD4 exome AF: 0.895 AC: 1307706 AN: 1461636 Hom.: 589133 Cov.: 51 AF XY: 0.897 AC XY: 652299 AN XY: 727152

African (AFR) AF: 0.438 AC: 14668 AN: 33466

American (AMR) AF: 0.920 AC: 41154 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 23612 AN: 26136

East Asian (EAS) AF: 0.977 AC: 38768 AN: 39698

South Asian (SAS) AF: 0.917 AC: 79113 AN: 86246

European-Finnish (FIN) AF: 0.912 AC: 48710 AN: 53418

Middle Eastern (MID) AF: 0.850 AC: 4902 AN: 5768

European-Non Finnish (NFE) AF: 0.903 AC: 1003627 AN: 1111806

Other (OTH) AF: 0.880 AC: 53152 AN: 60386

GnomAD4 genome AF: 0.779 AC: 118394 AN: 152004 Hom.: 49255 Cov.: 30 AF XY: 0.785 AC XY: 58296 AN XY: 74288

African (AFR) AF: 0.454 AC: 18789 AN: 41396

American (AMR) AF: 0.874 AC: 13342 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 3125 AN: 3472

East Asian (EAS) AF: 0.984 AC: 5068 AN: 5150

South Asian (SAS) AF: 0.914 AC: 4398 AN: 4812

European-Finnish (FIN) AF: 0.915 AC: 9681 AN: 10582

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.901 AC: 61299 AN: 68008

Other (OTH) AF: 0.805 AC: 1696 AN: 2106

Alfa AF: 0.862 Hom.: 191760

Bravo AF: 0.761

TwinsUK AF: 0.906 AC: 3359

ALSPAC AF: 0.907 AC: 3495

ESP6500AA AF: 0.470 AC: 2071

ESP6500EA AF: 0.901 AC: 7752

ExAC AF: 0.875 AC: 106274

Asia WGS AF: 0.895 AC: 3113 AN: 3478

EpiCase AF: 0.901

EpiControl AF: 0.901

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Parietal foramina 1 Benign:3

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Craniosynostosis 2 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Oct 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21362336) -

Cranium bifidum occultum Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.071
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.23
Sift	Benign	0.11	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.20
MPC		0.46
ClinPred		0.0083	T
GERP RS		5.3
Varity_R		0.24
gMVP		0.40
Mutation Taster		=90/10	polymorphism (auto)

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: rs4242182; hg19: chr5-174156168; COSMIC: COSV53327173;