5-174725097-G-A

Variant names:

• chr5-174725097-G-A
• rs2048152
• NM_002449.5:c.379+59G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002449.5(MSX2):​c.379+59G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.89 in 1,590,150 control chromosomes in the GnomAD database, including 634,764 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.81 (51661 hom., cov: 32)
  • Exomes 𝑓: 0.90 (583103 hom.)
• Consequence: MSX2 NM_002449.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.374
• Publications: 7 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-174725097-G-A is Benign according to our data. Variant chr5-174725097-G-A is described in ClinVar as Benign. ClinVar VariationId is 1246644.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSX2	NM_002449.5	MANE Select	c.379+59G>A		intron	N/A	NP_002440.2
	MSX2	NM_001363626.2		c.*3+30G>A		intron	N/A	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.379+59G>A		intron	N/A	ENSP00000239243.5	P35548
	MSX2	ENST00000507785.2	TSL:2	c.*3+30G>A		intron	N/A	ENSP00000427425.1	D6RIS4

Frequencies

GnomAD3 genomes AF: 0.809 AC: 122891 AN: 151910 Hom.: 51651 Cov.: 32

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.884

Gnomad ASJ AF: 0.910

Gnomad EAS AF: 0.983

Gnomad SAS AF: 0.905

Gnomad FIN AF: 0.914

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.903

Gnomad OTH AF: 0.835

GnomAD2 exomes AF: 0.898 AC: 180895 AN: 201546 AF XY: 0.901

Gnomad AFR exome AF: 0.557

Gnomad AMR exome AF: 0.933

Gnomad ASJ exome AF: 0.914

Gnomad EAS exome AF: 0.983

Gnomad FIN exome AF: 0.916

Gnomad NFE exome AF: 0.905

Gnomad OTH exome AF: 0.900

GnomAD4 exome AF: 0.899 AC: 1292157 AN: 1438122 Hom.: 583103 Cov.: 41 AF XY: 0.900 AC XY: 642383 AN XY: 713452

African (AFR) AF: 0.543 AC: 17993 AN: 33118

American (AMR) AF: 0.925 AC: 37285 AN: 40294

Ashkenazi Jewish (ASJ) AF: 0.912 AC: 22957 AN: 25178

East Asian (EAS) AF: 0.976 AC: 37972 AN: 38898

South Asian (SAS) AF: 0.912 AC: 74761 AN: 81988

European-Finnish (FIN) AF: 0.912 AC: 45722 AN: 50112

Middle Eastern (MID) AF: 0.860 AC: 4885 AN: 5682

European-Non Finnish (NFE) AF: 0.904 AC: 997683 AN: 1103256

Other (OTH) AF: 0.888 AC: 52899 AN: 59596

GnomAD4 genome AF: 0.809 AC: 122943 AN: 152028 Hom.: 51661 Cov.: 32 AF XY: 0.813 AC XY: 60434 AN XY: 74330

African (AFR) AF: 0.556 AC: 23068 AN: 41460

American (AMR) AF: 0.884 AC: 13532 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 3158 AN: 3470

East Asian (EAS) AF: 0.983 AC: 5051 AN: 5136

South Asian (SAS) AF: 0.905 AC: 4356 AN: 4814

European-Finnish (FIN) AF: 0.914 AC: 9687 AN: 10594

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.903 AC: 61344 AN: 67938

Other (OTH) AF: 0.829 AC: 1750 AN: 2112

Alfa AF: 0.865 Hom.: 10587

Bravo AF: 0.795

Asia WGS AF: 0.891 AC: 3100 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.9
DANN	Benign	0.97
PhyloP100		-0.37
PromoterAI		0.031	Neutral
Mutation Taster		=100/0	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: rs2048152; hg19: chr5-174152100;