NM_002449.5:c.386T>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 49255 hom., cov: 30)

Exomes 𝑓: 0.89 ( 589133 hom. )

Consequence

MSX2
NM_002449.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.52

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr5-174729165-T-C is described in Lovd as [Benign].

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 link	c.386T>C	p.Met129Thr	missense_variant	Exon 2 of 2	ENST00000239243.7	NP_002440.2	P35548
MSX2	NM_001363626.2 link	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 link	c.386T>C	p.Met129Thr	missense_variant	Exon 2 of 2	1	NM_002449.5	ENSP00000239243.5		P35548
MSX2	ENST00000507785.2 link	c.*10T>C		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000427425.1		D6RIS4

Frequencies

GnomAD3 genomes

AF:

0.779

AC:

118356

AN:

151886

Hom.:

49247

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.885

AC:

222305

AN:

251302

Hom.:

100109

AF XY:

0.892

AC XY:

121205

AN XY:

135852

show subpopulations

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 SAS exome

AF:

0.918

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.:

AF XY:

0.897

AC XY:

652299

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.438

Gnomad4 AMR exome

AF:

0.920

Gnomad4 ASJ exome

AF:

0.903

Gnomad4 EAS exome

AF:

0.977

Gnomad4 SAS exome

AF:

0.917

Gnomad4 FIN exome

AF:

0.912

Gnomad4 NFE exome

AF:

0.903

Gnomad4 OTH exome

AF:

0.880

GnomAD4 genome

AF:

0.779

AC:

118394

AN:

152004

Hom.:

49255

Cov.:

AF XY:

0.785

AC XY:

58296

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.454

Gnomad4 AMR

AF:

0.874

Gnomad4 ASJ

AF:

0.900

Gnomad4 EAS

AF:

0.984

Gnomad4 SAS

AF:

0.914

Gnomad4 FIN

AF:

0.915

Gnomad4 NFE

AF:

0.901

Gnomad4 OTH

AF:

0.805

Alfa

AF:

0.883

Hom.:

143824

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

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Parietal foramina 1

Benign:3

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. -

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

- -

Craniosynostosis 2

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.32

Eigen

Benign

-0.12

Eigen_PC

Benign

0.071

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.71

MetaRNN

Benign

6.9e-7

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.0

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.5

REVEL

Benign

0.23

Sift

Benign

0.11

Sift4G

Benign

0.45

Polyphen

0.0

Vest4

0.20

MPC

0.46

ClinPred

0.0083

GERP RS

5.3

Varity_R

0.24

gMVP

0.40

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over