2-236167566-C-G

Position:

• chr2-236167566-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000306318.5(GBX2):​c.406G>C​(p.Gly136Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000796 in 1,597,906 control chromosomes in the GnomAD database, including 1 homozygotes. 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. G136D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (1 hom.)
• Consequence: GBX2 ENST00000306318.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.763

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14743325).
• BS2: High AC in GnomAd4 at 81 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBX2	NM_001485.4	c.406G>C	p.Gly136Arg	missense_variant	1/2	ENST00000306318.5	NP_001476.2
GBX2	NM_001301687.2	c.406G>C	p.Gly136Arg	missense_variant	1/3		NP_001288616.1
GBX2	XM_047443907.1	c.406G>C	p.Gly136Arg	missense_variant	1/4		XP_047299863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBX2	ENST00000306318.5	c.406G>C	p.Gly136Arg	missense_variant	1/2	1	NM_001485.4	ENSP00000302251	P1
GBX2-AS1	ENST00000415226.1	n.120C>G		non_coding_transcript_exon_variant	1/4	4

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000571 AC: 124 AN: 217158 Hom.: 0 AF XY: 0.000498 AC XY: 60 AN XY: 120538

Gnomad AFR exome AF: 0.0000842

Gnomad AMR exome AF: 0.000334

Gnomad ASJ exome AF: 0.000869

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000174

Gnomad FIN exome AF: 0.000591

Gnomad NFE exome AF: 0.000912

Gnomad OTH exome AF: 0.000367

GnomAD4 exome AF: 0.000824 AC: 1191 AN: 1445706 Hom.: 1 Cov.: 34 AF XY: 0.000801 AC XY: 576 AN XY: 718796

Gnomad4 AFR exome AF: 0.000124

Gnomad4 AMR exome AF: 0.000341

Gnomad4 ASJ exome AF: 0.00101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000377

Gnomad4 FIN exome AF: 0.000671

Gnomad4 NFE exome AF: 0.000924

Gnomad4 OTH exome AF: 0.000937

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31 AN XY: 74416

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000909 Hom.: 0

Bravo AF: 0.000457

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000596 AC: 5

ExAC AF: 0.000479 AC: 57

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

Jun 18, 2021

The c.406G>C (p.G136R) alteration is located in exon 1 (coding exon 1) of the GBX2 gene. This alteration results from a G to C substitution at nucleotide position 406, causing the glycine (G) at amino acid position 136 to be replaced by an arginine (R). 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	0.30
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	0.53	N;N
REVEL	Uncertain	0.49
Sift	Benign	0.21	T;D
Sift4G	Benign	0.30	T;D
Polyphen		0.97	D;D
Vest4		0.43
MVP		0.95
ClinPred		0.13	T
GERP RS		4.6
Varity_R		0.22
gMVP		0.35

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

Other links and lift over

dbSNP: rs183456996; hg19: chr2-237076209;