2-236167566-C-T

Variant names:

• chr2-236167566-C-T
• rs183456996
• NM_001485.4:c.406G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001485.4(GBX2):​c.406G>A​(p.Gly136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GBX2 NM_001485.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.763
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27956277).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001485.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBX2	NM_001485.4	MANE Select	c.406G>A	p.Gly136Ser	missense	Exon 1 of 2	NP_001476.2
	GBX2	NM_001301687.2		c.406G>A	p.Gly136Ser	missense	Exon 1 of 3	NP_001288616.1	F8VY47
	GBX2-AS1	NR_186035.1		n.125C>T		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBX2	ENST00000306318.5	TSL:1 MANE Select	c.406G>A	p.Gly136Ser	missense	Exon 1 of 2	ENSP00000302251.4	P52951
	GBX2	ENST00000551105.1	TSL:1	c.406G>A	p.Gly136Ser	missense	Exon 1 of 3	ENSP00000448747.1	F8VY47
	GBX2-AS1	ENST00000415226.1	TSL:4	n.120C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445708 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 718796

African (AFR) AF: 0.00 AC: 0 AN: 32340

American (AMR) AF: 0.00 AC: 0 AN: 43930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 39028

South Asian (SAS) AF: 0.00 AC: 0 AN: 84856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106786

Other (OTH) AF: 0.0000167 AC: 1 AN: 59762

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.014
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.76
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	0.34	N
REVEL	Uncertain	0.34
Sift	Benign	0.15	T
Sift4G	Benign	0.71	T
Polyphen		0.29	B
Vest4		0.13
MutPred		0.25		Loss of catalytic residue at G136 (P = 8e-04)
MVP		0.92
ClinPred		0.82	D
GERP RS		4.6
PromoterAI		0.056	Neutral
Varity_R		0.19
gMVP		0.25
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs183456996; hg19: chr2-237076209;