Genetic Variant GBX2:p.Arg125Cys (chr2-236167599-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001485.4(GBX2):c.373C>T(p.Arg125Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R125G) 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.32

Publications

0 publications found

Variant links:

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 links:

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

GBX2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.756

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GBX2	NM_001485.4	MANE Select	c.373C>T	p.Arg125Cys	missense	Exon 1 of 2	NP_001476.2
GBX2	NM_001301687.2		c.373C>T	p.Arg125Cys	missense	Exon 1 of 3	NP_001288616.1	F8VY47
GBX2-AS1	NR_186035.1		n.158G>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GBX2	ENST00000306318.5	TSL:1 MANE Select	c.373C>T	p.Arg125Cys	missense	Exon 1 of 2	ENSP00000302251.4	P52951
GBX2	ENST00000551105.1	TSL:1	c.373C>T	p.Arg125Cys	missense	Exon 1 of 3	ENSP00000448747.1	F8VY47
GBX2-AS1	ENST00000415226.1	TSL:4	n.153G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442156

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717158

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32188

American (AMR)

AF:

0.0000228

AC:

AN:

43784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25716

East Asian (EAS)

AF:

0.00

AC:

AN:

38876

South Asian (SAS)

AF:

0.00

AC:

AN:

84828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5462

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106238

Other (OTH)

AF:

0.00

AC:

AN:

59608

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.76

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

2.0

PhyloP100

1.3

PrimateAI

Pathogenic

0.97

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.61

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.50

MutPred

0.28

Loss of methylation at R125 (P = 0.0384)

MVP

0.97

ClinPred

0.96

GERP RS

4.5

PromoterAI

0.13

Neutral

(source)

Varity_R

0.51

gMVP

0.51

Mutation Taster

=44/56

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over