5-174730759-G-C

Variant names:

• chr5-174730759-G-C
• rs2890849
• NM_002449.5:c.*1176G>C

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.*1176G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 152,444 control chromosomes in the GnomAD database, including 49,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.80 (49754 hom., cov: 32)
  • Exomes 𝑓: 0.83 (151 hom.)
• Consequence: MSX2 NM_002449.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.288
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-174730759-G-C is Benign according to our data. Variant chr5-174730759-G-C is described in ClinVar as Benign. ClinVar VariationId is 352864.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSX2	NM_002449.5	c.*1176G>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000239243.7	NP_002440.2
MSX2	NM_001363626.2	c.*1604G>C		3_prime_UTR_variant	Exon 2 of 2		NP_001350555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSX2	ENST00000239243.7	c.*1176G>C		3_prime_UTR_variant	Exon 2 of 2	1	NM_002449.5	ENSP00000239243.5

Frequencies

GnomAD3 genomes AF: 0.802 AC: 121852 AN: 151890 Hom.: 49736 Cov.: 32

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.865

Gnomad ASJ AF: 0.839

Gnomad EAS AF: 0.985

Gnomad SAS AF: 0.937

Gnomad FIN AF: 0.846

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.858

Gnomad OTH AF: 0.822

GnomAD4 exome AF: 0.828 AC: 361 AN: 436 Hom.: 151 Cov.: 0 AF XY: 0.840 AC XY: 220 AN XY: 262

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.828 AC: 356 AN: 430

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.802 AC: 121919 AN: 152008 Hom.: 49754 Cov.: 32 AF XY: 0.807 AC XY: 59921 AN XY: 74288

African (AFR) AF: 0.632 AC: 26153 AN: 41362

American (AMR) AF: 0.865 AC: 13226 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.839 AC: 2910 AN: 3470

East Asian (EAS) AF: 0.985 AC: 5104 AN: 5184

South Asian (SAS) AF: 0.937 AC: 4519 AN: 4824

European-Finnish (FIN) AF: 0.846 AC: 8931 AN: 10560

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

European-Non Finnish (NFE) AF: 0.858 AC: 58382 AN: 68012

Other (OTH) AF: 0.816 AC: 1712 AN: 2098

Alfa AF: 0.789 Hom.: 2877

Bravo AF: 0.795

Asia WGS AF: 0.919 AC: 3194 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Craniosynostosis 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Parietal foramina 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.83
DANN	Benign	0.57
PhyloP100		-0.29
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: rs2890849; hg19: chr5-174157762;