chr5-174724781-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002449.5(MSX2):​c.122A>T​(p.Lys41Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MSX2
NM_002449.5 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 2.34
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MSX2NM_002449.5 linkuse as main transcriptc.122A>T p.Lys41Met missense_variant 1/2 ENST00000239243.7
MSX2NM_001363626.2 linkuse as main transcriptc.122A>T p.Lys41Met missense_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MSX2ENST00000239243.7 linkuse as main transcriptc.122A>T p.Lys41Met missense_variant 1/21 NM_002449.5 P1
MSX2ENST00000507785.2 linkuse as main transcriptc.122A>T p.Lys41Met missense_variant 1/22

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Craniosynostosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Parietal foramina 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D;.
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.79
T;T
M_CAP
Pathogenic
0.56
D
MetaRNN
Uncertain
0.67
D;D
MetaSVM
Uncertain
0.75
D
MutationAssessor
Uncertain
2.7
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-2.2
N;D
REVEL
Uncertain
0.51
Sift
Uncertain
0.0070
D;D
Sift4G
Uncertain
0.032
D;D
Polyphen
1.0
D;.
Vest4
0.53
MutPred
0.28
Loss of ubiquitination at K41 (P = 0.0023);Loss of ubiquitination at K41 (P = 0.0023);
MVP
0.98
MPC
1.2
ClinPred
0.97
D
GERP RS
4.1
Varity_R
0.31
gMVP
0.59

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.

Other links and lift over

dbSNP: rs1760740243; hg19: chr5-174151784; API