5-174724643-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.457

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd at 4420 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.0291

AC:

4420

AN:

152042

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0332

AC XY:

23488

AN XY:

706880

show subpopulations

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.:

Cov.:

AF XY:

0.0298

AC XY:

2217

AN XY:

74422

show subpopulations

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.:

Bravo

AF:

0.0257

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

Cadd

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over