NM_002449.5:c.23A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_002449.5(MSX2):c.23A>G(p.Asn8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,587,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N8H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

MSX2
NM_002449.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.333

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

craniosynostosis 2
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Orphanet
parietal foramina
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
parietal foramina with cleidocranial dysplasia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
parietal foramina 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

MSX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011775404).

BP6

Variant 5-174724682-A-G is Benign according to our data. Variant chr5-174724682-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2026310.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000265 (40/150866) while in subpopulation AFR AF = 0.00092 (38/41312). AF 95% confidence interval is 0.000689. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 40 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002449.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX2	NM_002449.5	MANE Select	c.23A>G	p.Asn8Ser	missense	Exon 1 of 2	NP_002440.2
	MSX2	NM_001363626.2		c.23A>G	p.Asn8Ser	missense	Exon 1 of 2	NP_001350555.1	D6RIS4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX2	ENST00000239243.7	TSL:1 MANE Select	c.23A>G	p.Asn8Ser	missense	Exon 1 of 2	ENSP00000239243.5	P35548
	MSX2	ENST00000507785.2	TSL:2	c.23A>G	p.Asn8Ser	missense	Exon 1 of 2	ENSP00000427425.1	D6RIS4

Frequencies

GnomAD3 genomes

AF:

0.000265

AC:

AN:

150740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000922

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000434

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000561

AC:

AN:

213940

AF XY:

0.0000427

show subpopulations

Gnomad AFR exome

AF:

0.000846

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000278

AC:

AN:

1436784

Hom.:

Cov.:

AF XY:

0.0000196

AC XY:

AN XY:

713220

show subpopulations

African (AFR)

AF:

0.00109

AC:

AN:

32906

American (AMR)

AF:

0.00

AC:

AN:

42194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25514

East Asian (EAS)

AF:

0.00

AC:

AN:

38766

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83428

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50636

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4666

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1099582

Other (OTH)

AF:

0.0000338

AC:

AN:

59092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000265

AC:

AN:

150866

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

73730

show subpopulations

African (AFR)

AF:

0.000920

AC:

AN:

41312

American (AMR)

AF:

0.00

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

4954

South Asian (SAS)

AF:

0.000434

AC:

AN:

4606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67640

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000388

Hom.:

Bravo

AF:

0.000261

ESP6500AA

AF:

0.000700

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000585

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cranium bifidum occultum (1)

MSX2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.54

CADD

Benign

4.5

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.24

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.61

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-0.34

PhyloP100

0.33

PrimateAI

Benign

0.40

PROVEAN

Benign

0.17

REVEL

Benign

0.17

Sift

Benign

0.49

Sift4G

Benign

0.68

Polyphen

0.0

Vest4

0.081

MVP

0.62

MPC

0.31

ClinPred

0.0083

GERP RS

-4.1

PromoterAI

0.048

Neutral

(source)

Varity_R

0.021

gMVP

0.22

Mutation Taster

=94/6

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over