Variant 2-236166276-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000306318.5(GBX2):c.685G>A(p.Glu229Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000525 in 152,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Consequence

GBX2
ENST00000306318.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.95

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17113549).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GBX2	NM_001485.4 linkuse as main transcript	c.685G>A	p.Glu229Lys	missense_variant	2/2	ENST00000306318.5	NP_001476.2
GBX2	XM_047443907.1 linkuse as main transcript	c.685G>A	p.Glu229Lys	missense_variant	2/4		XP_047299863.1
GBX2	NM_001301687.2 linkuse as main transcript	c.*53G>A		3_prime_UTR_variant	3/3		NP_001288616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GBX2	ENST00000306318.5 linkuse as main transcript	c.685G>A	p.Glu229Lys	missense_variant	2/2	1	NM_001485.4	ENSP00000302251	P1
GBX2	ENST00000551105.1 linkuse as main transcript	c.*53G>A		3_prime_UTR_variant	3/3	1		ENSP00000448747
GBX2	ENST00000465889.1 linkuse as main transcript	n.354G>A		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.000151

ExAC

AF:

0.00000824

AC:

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

Jan 19, 2024

The c.685G>A (p.E229K) alteration is located in exon 2 (coding exon 2) of the GBX2 gene. This alteration results from a G to A substitution at nucleotide position 685, causing the glutamic acid (E) at amino acid position 229 to be replaced by a lysine (K). 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

Benign

0.33

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.17

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.41

Sift

Benign

0.13

Sift4G

Benign

0.30

Polyphen

0.28

Vest4

0.23

MutPred

0.31

Gain of ubiquitination at E229 (P = 0.0037);

MVP

0.83

ClinPred

0.44

GERP RS

4.3

Varity_R

0.27

gMVP

0.25

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