5-174724643-C-A

Variant names:

• chr5-174724643-C-A
• rs4647952
• NM_002449.5:c.-17C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002449.5(MSX2):​c.-17C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,579,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MSX2 NM_002449.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.457
• Publications: 9 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).

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.-17C>A		5_prime_UTR	Exon 1 of 2	NP_002440.2
	MSX2	NM_001363626.2		c.-17C>A		5_prime_UTR	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.-17C>A		5_prime_UTR	Exon 1 of 2	ENSP00000239243.5	P35548
	MSX2	ENST00000507785.2	TSL:2	c.-17C>A		5_prime_UTR	Exon 1 of 2	ENSP00000427425.1	D6RIS4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1427366 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 706946

African (AFR) AF: 0.00 AC: 0 AN: 32860

American (AMR) AF: 0.00 AC: 0 AN: 39882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25476

East Asian (EAS) AF: 0.00 AC: 0 AN: 38234

South Asian (SAS) AF: 0.00 AC: 0 AN: 81966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4326

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1095742

Other (OTH) AF: 0.00 AC: 0 AN: 58954

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 19

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.93
PhyloP100		-0.46
PromoterAI		-0.25	Neutral

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: rs4647952; hg19: chr5-174151646;