2-236167643-C-T

Variant names:

• chr2-236167643-C-T
• rs368198659
• NM_001485.4:c.329G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001485.4(GBX2):​c.329G>A​(p.Gly110Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,190 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. G110V) 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: 1.71
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24676242).

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.329G>A	p.Gly110Asp	missense	Exon 1 of 2	NP_001476.2
	GBX2	NM_001301687.2		c.329G>A	p.Gly110Asp	missense	Exon 1 of 3	NP_001288616.1	F8VY47
	GBX2-AS1	NR_186035.1		n.202C>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.329G>A	p.Gly110Asp	missense	Exon 1 of 2	ENSP00000302251.4	P52951
	GBX2	ENST00000551105.1	TSL:1	c.329G>A	p.Gly110Asp	missense	Exon 1 of 3	ENSP00000448747.1	F8VY47
	GBX2-AS1	ENST00000415226.1	TSL:4	n.197C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441190 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 717142

African (AFR) AF: 0.00 AC: 0 AN: 31622

American (AMR) AF: 0.00 AC: 0 AN: 43992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25686

East Asian (EAS) AF: 0.00 AC: 0 AN: 38564

South Asian (SAS) AF: 0.00 AC: 0 AN: 84754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5484

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1106824

Other (OTH) AF: 0.00 AC: 0 AN: 59658

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.0017
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.32
Sift	Benign	0.40	T
Sift4G	Benign	0.48	T
Polyphen		0.0030	B
Vest4		0.25
MutPred		0.16		Gain of solvent accessibility (P = 0.0638)
MVP		0.84
ClinPred		0.58	D
GERP RS		4.8
PromoterAI		-0.062	Neutral
Varity_R		0.18
gMVP		0.49
Mutation Taster		=49/51	disease causing

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: rs368198659; hg19: chr2-237076286;