5-174724682-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002449.5(MSX2):c.23A>G(p.Asn8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,587,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N8H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: MSX2 NM_002449.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.333

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011775404).
• BP6: Variant 5-174724682-A-G is Benign according to our data. Variant chr5-174724682-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2026310.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000265 (40/150866) while in subpopulation AFR AF= 0.00092 (38/41312). AF 95% confidence interval is 0.000689. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSX2	NM_002449.5	c.23A>G	p.Asn8Ser	missense_variant	1/2	ENST00000239243.7
MSX2	NM_001363626.2	c.23A>G	p.Asn8Ser	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSX2	ENST00000239243.7	c.23A>G	p.Asn8Ser	missense_variant	1/2	1	NM_002449.5	P1
MSX2	ENST00000507785.2	c.23A>G	p.Asn8Ser	missense_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000265 AC: 40 AN: 150740 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000922

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000434

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000561 AC: 12 AN: 213940 Hom.: 0 AF XY: 0.0000427 AC XY: 5 AN XY: 117128

Gnomad AFR exome AF: 0.000846

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000727

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000278 AC: 40 AN: 1436784 Hom.: 0 Cov.: 32 AF XY: 0.0000196 AC XY: 14 AN XY: 713220

Gnomad4 AFR exome AF: 0.00109

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.09e-7

Gnomad4 OTH exome AF: 0.0000338

GnomAD4 genome AF: 0.000265 AC: 40 AN: 150866 Hom.: 0 Cov.: 32 AF XY: 0.000203 AC XY: 15 AN XY: 73730

Gnomad4 AFR AF: 0.000920

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000434

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000151 Hom.: 0

Bravo AF: 0.000261

ESP6500AA AF: 0.000700 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000585 AC: 7

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cranium bifidum occultum Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 24, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	4.5
Dann	Benign	0.24
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.61	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.34	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.17	N;N
REVEL	Benign	0.17
Sift	Benign	0.49	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.0	B;.
Vest4		0.081
MVP		0.62
MPC		0.31
ClinPred		0.0083	T
GERP RS		-4.1
Varity_R		0.021
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs367636705; hg19: chr5-174151685;