5-174724754-A-T

Position:

chr5-174724754-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002449.5(MSX2):c.95A>T(p.Glu32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,569,056 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

MSX2
NM_002449.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.08

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24444926).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSX2	NM_002449.5 linkuse as main transcript	c.95A>T	p.Glu32Val	missense_variant	1/2	ENST00000239243.7
MSX2	NM_001363626.2 linkuse as main transcript	c.95A>T	p.Glu32Val	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSX2	ENST00000239243.7 linkuse as main transcript	c.95A>T	p.Glu32Val	missense_variant	1/2	1	NM_002449.5	P1
MSX2	ENST00000507785.2 linkuse as main transcript	c.95A>T	p.Glu32Val	missense_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000238

AC:

AN:

167862

Hom.:

AF XY:

0.0000218

AC XY:

AN XY:

91562

show subpopulations

Gnomad AFR exome

AF:

0.000238

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000149

Gnomad OTH exome

AF:

0.000219

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1417040

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

700780

show subpopulations

Gnomad4 AFR exome

AF:

0.000617

Gnomad4 AMR exome

AF:

0.0000263

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000275

Gnomad4 OTH exome

AF:

0.000119

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152016

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000176

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2022

The c.95A>T (p.E32V) alteration is located in exon 1 (coding exon 1) of the MSX2 gene. This alteration results from a A to T substitution at nucleotide position 95, causing the glutamic acid (E) at amino acid position 32 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cranium bifidum occultum

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 32 of the MSX2 protein (p.Glu32Val). This variant is present in population databases (rs780593593, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MSX2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1468184). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.47

T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.71

T;T

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.24

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

0.89

N;N

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.26

Sift

Benign

0.062

T;D

Sift4G

Benign

0.14

T;T

Polyphen

0.013

B;.

Vest4

0.35

MutPred

0.29

Loss of solvent accessibility (P = 0.0013);Loss of solvent accessibility (P = 0.0013);

MVP

0.99

MPC

0.46

ClinPred

0.079

GERP RS

3.2

Varity_R

0.13

gMVP

0.56

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