Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001374353.1(GLI2):c.3539G>A(p.Gly1180Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000863 in 1,612,168 control chromosomes in the GnomAD database, including 19 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1180C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0048 ( 12 hom., cov: 34)

Exomes 𝑓: 0.00046 ( 7 hom. )

Consequence

GLI2
NM_001374353.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.274

Publications

4 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=0.0032847226).

BP6

Variant 2-120989504-G-A is Benign according to our data. Variant chr2-120989504-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00477 (726/152340) while in subpopulation AFR AF = 0.0169 (704/41584). AF 95% confidence interval is 0.0159. There are 12 homozygotes in GnomAd4. There are 349 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374353.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLI2	NM_001374353.1	MANE Select	c.3539G>A	p.Gly1180Asp	missense	Exon 14 of 14	NP_001361282.1
GLI2	NM_001371271.1		c.3590G>A	p.Gly1197Asp	missense	Exon 14 of 14	NP_001358200.1
GLI2	NM_005270.5		c.3590G>A	p.Gly1197Asp	missense	Exon 14 of 14	NP_005261.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLI2	ENST00000361492.9	TSL:1 MANE Select	c.3539G>A	p.Gly1180Asp	missense	Exon 14 of 14	ENSP00000354586.5
GLI2	ENST00000452319.6	TSL:5	c.3590G>A	p.Gly1197Asp	missense	Exon 13 of 13	ENSP00000390436.1
GLI2	ENST00000341310.10	TSL:2	n.*2638G>A		non_coding_transcript_exon	Exon 10 of 10	ENSP00000344473.6

Frequencies

GnomAD3 genomes

AF:

0.00475

AC:

723

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00124

AC:

300

AN:

241794

AF XY:

0.000973

show subpopulations

Gnomad AFR exome

AF:

0.0185

Gnomad AMR exome

AF:

0.000584

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000505

GnomAD4 exome

AF:

0.000456

AC:

665

AN:

1459828

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

293

AN XY:

726226

show subpopulations

African (AFR)

AF:

0.0172

AC:

577

AN:

33466

American (AMR)

AF:

0.000627

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111678

Other (OTH)

AF:

0.000763

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

140

186

233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00477

AC:

726

AN:

152340

Hom.:

Cov.:

AF XY:

0.00469

AC XY:

349

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0169

AC:

704

AN:

41584

American (AMR)

AF:

0.000849

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00167

Hom.:

Bravo

AF:

0.00541

ESP6500AA

AF:

0.0144

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00142

AC:

172

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

GLI2-related disorder (1)

Holoprosencephaly 9 (1)

Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.1

(source)

DANN

Benign

0.45

DEOGEN2

Uncertain

0.46

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

-0.27

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.0

REVEL

Benign

0.029

Sift

Benign

0.30

Sift4G

Benign

0.31

Polyphen

0.0

Vest4

0.067

MVP

0.15

MPC

0.44

ClinPred

0.0049

GERP RS

-2.4

Varity_R

0.049

gMVP

0.085

Mutation Taster

=97/3

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

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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

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over