5-174724762-G-C

Variant names:

• chr5-174724762-G-C
• rs1210698589
• NM_002449.5:c.103G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002449.5(MSX2):​c.103G>C​(p.Ala35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,409,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MSX2 NM_002449.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.09
• Publications: 1 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16744903).

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.103G>C	p.Ala35Pro	missense	Exon 1 of 2	NP_002440.2
	MSX2	NM_001363626.2		c.103G>C	p.Ala35Pro	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.103G>C	p.Ala35Pro	missense	Exon 1 of 2	ENSP00000239243.5	P35548
	MSX2	ENST00000507785.2	TSL:2	c.103G>C	p.Ala35Pro	missense	Exon 1 of 2	ENSP00000427425.1	D6RIS4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000631 AC: 1 AN: 158566 AF XY: 0.0000116

Gnomad AFR exome AF: 0.00

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: 0.000227

GnomAD4 exome AF: 0.00000284 AC: 4 AN: 1409478 Hom.: 0 Cov.: 36 AF XY: 0.00000144 AC XY: 1 AN XY: 696452

African (AFR) AF: 0.00 AC: 0 AN: 32160

American (AMR) AF: 0.0000543 AC: 2 AN: 36862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25242

East Asian (EAS) AF: 0.00 AC: 0 AN: 36944

South Asian (SAS) AF: 0.00 AC: 0 AN: 80416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4964

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1085934

Other (OTH) AF: 0.00 AC: 0 AN: 58356

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	MSX2-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.081
Sift	Benign	0.33	T
Sift4G	Benign	0.28	T
Polyphen		0.0020	B
Vest4		0.18
MutPred		0.25		Gain of loop (P = 0.0097)
MVP		0.92
MPC		0.84
ClinPred		0.093	T
GERP RS		2.2
PromoterAI		-0.015	Neutral
Varity_R		0.12
gMVP		0.44
Mutation Taster		=86/14	polymorphism

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: rs1210698589; hg19: chr5-174151765;