Genetic Variant GLI2:p.Ala835Pro (chr2-120988468-G-C) – 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_001374353.1(GLI2):c.2503G>C(p.Ala835Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,411,600 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. A835T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

GLI2
NM_001374353.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.49

Publications

5 publications found

Variant links:

Genes affected

GLI2 (HGNC:4318): (GLI family zinc finger 2) This gene encodes a protein which belongs to the C2H2-type zinc finger protein subclass of the Gli family. Members of this subclass are characterized as transcription factors which bind DNA through zinc finger motifs. These motifs contain conserved H-C links. Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling and they are implicated as potent oncogenes in the embryonal carcinoma cell. The protein encoded by this gene localizes to the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. The encoded protein is associated with several phenotypes- Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]

GLI2 Gene-Disease associations (from GenCC):

holoprosencephaly 9
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, Ambry Genetics
combined pituitary hormone deficiencies, genetic form
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
holoprosencephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GLI2 links:

Genome browser will be placed here

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, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI2	NM_001374353.1 link	c.2503G>C	p.Ala835Pro	missense_variant	Exon 14 of 14	ENST00000361492.9	NP_001361282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI2	ENST00000361492.9 link	c.2503G>C	p.Ala835Pro	missense_variant	Exon 14 of 14	1	NM_001374353.1	ENSP00000354586.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1411600

Hom.:

Cov.:

AF XY:

0.00000285

AC XY:

AN XY:

700972

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30244

American (AMR)

AF:

0.00

AC:

AN:

41552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25070

East Asian (EAS)

AF:

0.00

AC:

AN:

36304

South Asian (SAS)

AF:

0.00

AC:

AN:

81446

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1096746

Other (OTH)

AF:

0.0000341

AC:

AN:

58720

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Uncertain

0.40

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

.;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

7.5

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.033

D;D

Polyphen

1.0

D;D

Vest4

0.60

MutPred

0.21

Loss of stability (P = 0.0758);Loss of stability (P = 0.0758);

MVP

0.92

MPC

0.99

ClinPred

0.99

GERP RS

3.6

Varity_R

0.76

gMVP

0.60

Mutation Taster

=59/41

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over