5-174729165-T-C

Variant names:

• chr5-174729165-T-C
• rs4242182
• NM_002449.5:c.386T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M129R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.78 (49255 hom., cov: 30)
  • Exomes 𝑓: 0.89 (589133 hom.)
• Consequence: MSX2 NM_002449.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.52
• Publications: 44 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: Ambry Genetics, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• parietal foramina

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• parietal foramina with cleidocranial dysplasia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• parietal foramina 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 258657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX2	NM_002449.5	MANE Select	c.386T>C	p.Met129Thr	missense	Exon 2 of 2	NP_002440.2
	MSX2	NM_001363626.2		c.*10T>C		3_prime_UTR	Exon 2 of 2	NP_001350555.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX2	ENST00000239243.7	TSL:1 MANE Select	c.386T>C	p.Met129Thr	missense	Exon 2 of 2	ENSP00000239243.5
	MSX2	ENST00000507785.2	TSL:2	c.*10T>C		3_prime_UTR	Exon 2 of 2	ENSP00000427425.1

Frequencies

GnomAD3 genomes AF: 0.779 AC: 118356 AN: 151886 Hom.: 49247 Cov.: 30

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

GnomAD2 exomes AF: 0.885 AC: 222305 AN: 251302 AF XY: 0.892

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 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.: 51 AF XY: 0.897 AC XY: 652299 AN XY: 727152

African (AFR) AF: 0.438 AC: 14668 AN: 33466

American (AMR) AF: 0.920 AC: 41154 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 23612 AN: 26136

East Asian (EAS) AF: 0.977 AC: 38768 AN: 39698

South Asian (SAS) AF: 0.917 AC: 79113 AN: 86246

European-Finnish (FIN) AF: 0.912 AC: 48710 AN: 53418

Middle Eastern (MID) AF: 0.850 AC: 4902 AN: 5768

European-Non Finnish (NFE) AF: 0.903 AC: 1003627 AN: 1111806

Other (OTH) AF: 0.880 AC: 53152 AN: 60386

GnomAD4 genome AF: 0.779 AC: 118394 AN: 152004 Hom.: 49255 Cov.: 30 AF XY: 0.785 AC XY: 58296 AN XY: 74288

African (AFR) AF: 0.454 AC: 18789 AN: 41396

American (AMR) AF: 0.874 AC: 13342 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 3125 AN: 3472

East Asian (EAS) AF: 0.984 AC: 5068 AN: 5150

South Asian (SAS) AF: 0.914 AC: 4398 AN: 4812

European-Finnish (FIN) AF: 0.915 AC: 9681 AN: 10582

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.901 AC: 61299 AN: 68008

Other (OTH) AF: 0.805 AC: 1696 AN: 2106

Alfa AF: 0.862 Hom.: 191760

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Parietal foramina 1 (3)
-	-	2	Craniosynostosis 2 (2)
-	-	1	Cranium bifidum occultum (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.071
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.23
Sift	Benign	0.11	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.20
MPC		0.46
ClinPred		0.0083	T
GERP RS		5.3
Varity_R		0.24
gMVP		0.40
Mutation Taster		=90/10	polymorphism (auto)

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: rs4242182; hg19: chr5-174156168; COSMIC: COSV53327173;