Variant 2-236167599-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001485.4(GBX2):c.373C>G(p.Arg125Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,442,156 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GBX2
NM_001485.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32

Variant links:

Genes affected

GBX2 (HGNC:4186): (gastrulation brain homeobox 2) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of nervous system development and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including branching involved in blood vessel morphogenesis; nervous system development; and neural crest cell migration. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

GBX2 links:

GBX2-AS1 (HGNC:):

GBX2-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBX2	NM_001485.4 linkuse as main transcript	c.373C>G	p.Arg125Gly	missense_variant	1/2	ENST00000306318.5	NP_001476.2	P52951
GBX2	NM_001301687.2 linkuse as main transcript	c.373C>G	p.Arg125Gly	missense_variant	1/3		NP_001288616.1	F8VY47
GBX2	XM_047443907.1 linkuse as main transcript	c.373C>G	p.Arg125Gly	missense_variant	1/4		XP_047299863.1
GBX2-AS1	NR_186035.1 linkuse as main transcript	n.158G>C		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBX2	ENST00000306318.5 linkuse as main transcript	c.373C>G	p.Arg125Gly	missense_variant	1/2	1	NM_001485.4	ENSP00000302251.4		P52951

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000471

AC:

AN:

212288

Hom.:

AF XY:

0.00

AC XY:

AN XY:

118564

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000305

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1442156

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000228

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2024

The c.373C>G (p.R125G) alteration is located in exon 1 (coding exon 1) of the GBX2 gene. This alteration results from a C to G substitution at nucleotide position 373, causing the arginine (R) at amino acid position 125 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.79

T;T

M_CAP

Pathogenic

0.79

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

2.0

M;.

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-0.79

N;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.023

D;D

Sift4G

Uncertain

0.015

D;T

Polyphen

0.96

D;D

Vest4

0.60

MutPred

0.25

Loss of methylation at R125 (P = 0.0384);Loss of methylation at R125 (P = 0.0384);

MVP

0.97

ClinPred

0.73

GERP RS

4.5

Varity_R

0.58

gMVP

0.46

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

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