rs12711538

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001374353.1(GLI2):c.3865G>A(p.Asp1289Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 1,611,070 control chromosomes in the GnomAD database, including 391,822 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33527 hom., cov: 35)

Exomes 𝑓: 0.70 ( 358295 hom. )

Consequence

GLI2
NM_001374353.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.13

Publications

42 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.033025E-6).

BP6

Variant 2-120989830-G-A is Benign according to our data. Variant chr2-120989830-G-A is described in ClinVar as Benign. ClinVar VariationId is 95272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI2	NM_001374353.1 link	c.3865G>A	p.Asp1289Asn	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.3865G>A	p.Asp1289Asn	missense_variant	Exon 14 of 14	1	NM_001374353.1	ENSP00000354586.5		A0A7I2PJA1

Frequencies

GnomAD3 genomes

AF:

0.659

AC:

100139

AN:

152032

Hom.:

33512

Cov.:

show subpopulations

Gnomad AFR

AF:

0.581

Gnomad AMI

AF:

0.802

Gnomad AMR

AF:

0.647

Gnomad ASJ

AF:

0.681

Gnomad EAS

AF:

0.477

Gnomad SAS

AF:

0.504

Gnomad FIN

AF:

0.661

Gnomad MID

AF:

0.687

Gnomad NFE

AF:

0.730

Gnomad OTH

AF:

0.668

GnomAD2 exomes

AF:

0.645

AC:

159215

AN:

246908

AF XY:

0.646

show subpopulations

Gnomad AFR exome

AF:

0.577

Gnomad AMR exome

AF:

0.580

Gnomad ASJ exome

AF:

0.671

Gnomad EAS exome

AF:

0.464

Gnomad FIN exome

AF:

0.676

Gnomad NFE exome

AF:

0.727

Gnomad OTH exome

AF:

0.671

GnomAD4 exome

AF:

0.697

AC:

1016406

AN:

1458920

Hom.:

358295

Cov.:

AF XY:

0.692

AC XY:

502381

AN XY:

725534

show subpopulations

African (AFR)

AF:

0.574

AC:

19197

AN:

33448

American (AMR)

AF:

0.585

AC:

26079

AN:

44578

Ashkenazi Jewish (ASJ)

AF:

0.677

AC:

17631

AN:

26046

East Asian (EAS)

AF:

0.474

AC:

18800

AN:

39656

South Asian (SAS)

AF:

0.526

AC:

45297

AN:

86064

European-Finnish (FIN)

AF:

0.673

AC:

35253

AN:

52356

Middle Eastern (MID)

AF:

0.636

AC:

3666

AN:

5768

European-Non Finnish (NFE)

AF:

0.729

AC:

809840

AN:

1110754

Other (OTH)

AF:

0.675

AC:

40643

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

18422

36845

55267

73690

92112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19880

39760

59640

79520

99400

<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

AF:

0.658

AC:

100174

AN:

152150

Hom.:

33527

Cov.:

AF XY:

0.652

AC XY:

48522

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.580

AC:

24099

AN:

41522

American (AMR)

AF:

0.646

AC:

9887

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.681

AC:

2363

AN:

3470

East Asian (EAS)

AF:

0.476

AC:

2459

AN:

5164

South Asian (SAS)

AF:

0.504

AC:

2431

AN:

4822

European-Finnish (FIN)

AF:

0.661

AC:

7004

AN:

10594

Middle Eastern (MID)

AF:

0.697

AC:

205

AN:

294

European-Non Finnish (NFE)

AF:

0.730

AC:

49583

AN:

67966

Other (OTH)

AF:

0.670

AC:

1412

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1789

3577

5366

7154

8943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

798

1596

2394

3192

3990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.702

Hom.:

59648

Bravo

AF:

0.653

TwinsUK

AF:

0.718

AC:

2661

ALSPAC

AF:

0.723

AC:

2787

ESP6500AA

AF:

0.576

AC:

2536

ESP6500EA

AF:

0.728

AC:

6262

ExAC

AF:

0.644

AC:

78079

Asia WGS

AF:

0.499

AC:

1736

AN:

3478

EpiCase

AF:

0.735

EpiControl

AF:

0.735

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 09, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Holoprosencephaly 9

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.9

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0039

LIST_S2

Benign

0.24

.;T

MetaRNN

Benign

0.0000020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.5

N;N

PhyloP100

2.1

PrimateAI

Benign

0.35

PROVEAN

Benign

1.9

N;N

REVEL

Benign

0.081

Sift

Benign

1.0

T;T

Sift4G

Benign

0.92

T;T

Polyphen

0.0

B;B

Vest4

0.011

MPC

0.32

ClinPred

0.00087

GERP RS

2.1

Varity_R

0.039

gMVP

0.047

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over