Variant chr2-236167724-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001485.4(GBX2):c.248T>C(p.Ile83Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000231 in 1,555,596 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

GBX2
NM_001485.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.45

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:

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=0.27775306).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBX2	NM_001485.4 linkuse as main transcript	c.248T>C	p.Ile83Thr	missense_variant	1/2	ENST00000306318.5	NP_001476.2	P52951
GBX2	NM_001301687.2 linkuse as main transcript	c.248T>C	p.Ile83Thr	missense_variant	1/3		NP_001288616.1	F8VY47
GBX2	XM_047443907.1 linkuse as main transcript	c.248T>C	p.Ile83Thr	missense_variant	1/4		XP_047299863.1
GBX2-AS1	NR_186035.1 linkuse as main transcript	n.228+55A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBX2	ENST00000306318.5 linkuse as main transcript	c.248T>C	p.Ile83Thr	missense_variant	1/2	1	NM_001485.4	ENSP00000302251.4		P52951

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151296

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

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:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000388

AC:

AN:

180290

Hom.:

AF XY:

0.00000985

AC XY:

AN XY:

101564

show subpopulations

Gnomad AFR exome

AF:

0.000120

Gnomad AMR exome

AF:

0.000190

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:

0.0000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000221

AC:

AN:

1404300

Hom.:

Cov.:

AF XY:

0.0000158

AC XY:

AN XY:

697932

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000131

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:

0.0000212

Gnomad4 OTH exome

AF:

0.0000520

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151296

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73848

show subpopulations

Gnomad4 AFR

AF:

0.0000486

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:

0.0000442

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

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

Jun 17, 2022

The c.248T>C (p.I83T) alteration is located in exon 1 (coding exon 1) of the GBX2 gene. This alteration results from a T to C substitution at nucleotide position 248, causing the isoleucine (I) at amino acid position 83 to be replaced by a threonine (T). 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

Pathogenic

0.77

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

-0.043

Eigen_PC

Benign

0.093

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

T;T

M_CAP

Pathogenic

0.88

MetaRNN

Benign

0.28

T;T

MetaSVM

Uncertain

-0.029

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.96

PROVEAN

Benign

-0.40

N;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.0050

D;D

Sift4G

Benign

0.19

T;T

Polyphen

0.17

B;P

Vest4

0.30

MutPred

0.22

Gain of glycosylation at I83 (P = 0.0064);Gain of glycosylation at I83 (P = 0.0064);

MVP

0.86

ClinPred

0.42

GERP RS

4.7

Varity_R

0.45

gMVP

0.17

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