2-236167565-C-T

Position:

• chr2-236167565-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000306318.5(GBX2):​c.407G>A​(p.Gly136Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,188 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G136R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GBX2 ENST00000306318.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

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-AS1 (HGNC:55714): (GBX2 and ASB18 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28571802).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBX2	NM_001485.4	c.407G>A	p.Gly136Asp	missense_variant	1/2	ENST00000306318.5	NP_001476.2
GBX2	NM_001301687.2	c.407G>A	p.Gly136Asp	missense_variant	1/3		NP_001288616.1
GBX2	XM_047443907.1	c.407G>A	p.Gly136Asp	missense_variant	1/4		XP_047299863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBX2	ENST00000306318.5	c.407G>A	p.Gly136Asp	missense_variant	1/2	1	NM_001485.4	ENSP00000302251	P1
GBX2-AS1	ENST00000415226.1	n.119C>T		non_coding_transcript_exon_variant	1/4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446188 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 719100

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2024

The c.407G>A (p.G136D) alteration is located in exon 1 (coding exon 1) of the GBX2 gene. This alteration results from a G to A substitution at nucleotide position 407, causing the glycine (G) at amino acid position 136 to be replaced by an aspartic acid (D). 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	0.22
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	0.047
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.66	T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.34	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	0.12	N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.066	T;T
Polyphen		0.79	P;D
Vest4		0.26
MutPred		0.29		Loss of catalytic residue at G136 (P = 3e-04);Loss of catalytic residue at G136 (P = 3e-04);
MVP		0.92
ClinPred		0.94	D
GERP RS		4.6
Varity_R		0.29
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-237076208;