Variant 2-236167754-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The ENST00000306318.5(GBX2):c.218C>A(p.Ala73Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,462,926 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 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000038 ( 0 hom. )

Consequence

GBX2
ENST00000306318.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.54

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:55714): (GBX2 and ASB18 antisense RNA 1)

GBX2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29938728).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GBX2	NM_001485.4 linkuse as main transcript	c.218C>A	p.Ala73Glu	missense_variant	1/2	ENST00000306318.5	NP_001476.2
GBX2	NM_001301687.2 linkuse as main transcript	c.218C>A	p.Ala73Glu	missense_variant	1/3		NP_001288616.1
GBX2	XM_047443907.1 linkuse as main transcript	c.218C>A	p.Ala73Glu	missense_variant	1/4		XP_047299863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBX2	ENST00000306318.5 linkuse as main transcript	c.218C>A	p.Ala73Glu	missense_variant	1/2	1	NM_001485.4	ENSP00000302251	P1
GBX2-AS1	ENST00000415226.1 linkuse as main transcript	n.223+85G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151294

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000381

AC:

AN:

1311632

Hom.:

Cov.:

AF XY:

0.00000463

AC XY:

AN XY:

647792

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000469

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:

0.00000287

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151294

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73862

show subpopulations

Gnomad4 AFR

AF:

0.0000726

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000176

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

Dec 14, 2023

The c.218C>A (p.A73E) alteration is located in exon 1 (coding exon 1) of the GBX2 gene. This alteration results from a C to A substitution at nucleotide position 218, causing the alanine (A) at amino acid position 73 to be replaced by a glutamic acid (E). 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

0.35

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.093

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.70

T;T

M_CAP

Pathogenic

0.82

MetaRNN

Benign

0.30

T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

0.91

D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.56

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.065

T;D

Sift4G

Benign

0.34

T;T

Polyphen

0.68

P;P

Vest4

0.32

MutPred

0.17

Gain of catalytic residue at A73 (P = 0.0636);Gain of catalytic residue at A73 (P = 0.0636);

MVP

0.94

ClinPred

0.27

GERP RS

4.4

Varity_R

0.21

gMVP

0.29

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