chr2-236167460-T-C

Variant names:

• chr2-236167460-T-C
• rs377437929
• NM_001485.4:c.512A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001485.4(GBX2):​c.512A>G​(p.Gln171Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 151,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBX2 NM_001485.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.545
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20131513).
• BS2: High AC in GnomAd4 at 9 AD gene.

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.512A>G	p.Gln171Arg	missense	Exon 1 of 2	NP_001476.2
	GBX2	NM_001301687.2		c.512A>G	p.Gln171Arg	missense	Exon 1 of 3	NP_001288616.1	F8VY47
	GBX2-AS1	NR_186035.1		n.19T>C		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.512A>G	p.Gln171Arg	missense	Exon 1 of 2	ENSP00000302251.4	P52951
	GBX2	ENST00000551105.1	TSL:1	c.512A>G	p.Gln171Arg	missense	Exon 1 of 3	ENSP00000448747.1	F8VY47
	GBX2-AS1	ENST00000415226.1	TSL:4	n.14T>C		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.0000595 AC: 9 AN: 151370 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000218

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

GnomAD2 exomes AF: 0.00000499 AC: 1 AN: 200280 AF XY: 0.00000887

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000109

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1410246 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 701998

African (AFR) AF: 0.00 AC: 0 AN: 29230

American (AMR) AF: 0.00 AC: 0 AN: 42094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24374

East Asian (EAS) AF: 0.00 AC: 0 AN: 35432

South Asian (SAS) AF: 0.00 AC: 0 AN: 83398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4908

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093264

Other (OTH) AF: 0.00 AC: 0 AN: 58112

GnomAD4 genome AF: 0.0000595 AC: 9 AN: 151370 Hom.: 0 Cov.: 33 AF XY: 0.0000406 AC XY: 3 AN XY: 73926

African (AFR) AF: 0.000218 AC: 9 AN: 41220

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67788

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.000241 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.55
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.21
Sift	Benign	0.050	D
Sift4G	Benign	0.52	T
Polyphen		0.0060	B
Vest4		0.10
MVP		0.90
ClinPred		0.078	T
GERP RS		4.3
Varity_R		0.13
gMVP		0.32
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs377437929; hg19: chr2-237076103;