5-174724643-C-G

Position:

• chr5-174724643-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002449.5(MSX2):​c.-17C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,579,412 control chromosomes in the GnomAD database, including 1,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (80 hom., cov: 32)
  • Exomes 𝑓: 0.034 (933 hom.)
• Consequence: MSX2 NM_002449.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.457

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 5-174724643-C-G is Benign according to our data. Variant chr5-174724643-C-G is described in ClinVar as [Benign]. Clinvar id is 352836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.029 (4420/152160) while in subpopulation NFE AF= 0.0391 (2656/67974). AF 95% confidence interval is 0.0378. There are 80 homozygotes in gnomad4. There are 2217 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4420 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSX2	NM_002449.5	c.-17C>G		5_prime_UTR_variant	1/2	ENST00000239243.7
MSX2	NM_001363626.2	c.-17C>G		5_prime_UTR_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSX2	ENST00000239243.7	c.-17C>G		5_prime_UTR_variant	1/2	1	NM_002449.5	P1
MSX2	ENST00000507785.2	c.-17C>G		5_prime_UTR_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4420 AN: 152042 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.00587

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.0606

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0614

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0390

Gnomad OTH AF: 0.0335

GnomAD3 exomes AF: 0.0300 AC: 5776 AN: 192838 Hom.: 115 AF XY: 0.0291 AC XY: 3057 AN XY: 105170

Gnomad AFR exome AF: 0.00491

Gnomad AMR exome AF: 0.0206

Gnomad ASJ exome AF: 0.0551

Gnomad EAS exome AF: 0.0000682

Gnomad SAS exome AF: 0.0148

Gnomad FIN exome AF: 0.0599

Gnomad NFE exome AF: 0.0371

Gnomad OTH exome AF: 0.0376

GnomAD4 exome AF: 0.0338 AC: 48229 AN: 1427252 Hom.: 933 Cov.: 32 AF XY: 0.0332 AC XY: 23488 AN XY: 706880

Gnomad4 AFR exome AF: 0.00572

Gnomad4 AMR exome AF: 0.0219

Gnomad4 ASJ exome AF: 0.0568

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0146

Gnomad4 FIN exome AF: 0.0605

Gnomad4 NFE exome AF: 0.0358

Gnomad4 OTH exome AF: 0.0363

GnomAD4 genome AF: 0.0290 AC: 4420 AN: 152160 Hom.: 80 Cov.: 32 AF XY: 0.0298 AC XY: 2217 AN XY: 74422

Gnomad4 AFR AF: 0.00585

Gnomad4 AMR AF: 0.0330

Gnomad4 ASJ AF: 0.0606

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.0614

Gnomad4 NFE AF: 0.0391

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.0280 Hom.: 19

Bravo AF: 0.0257

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 24, 2018

- -

Craniosynostosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.53
CADD	Benign	15
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4647952; hg19: chr5-174151646;