rs2592595

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001374353.1(GLI2):c.801G>A(p.Ser267Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.959 in 1,613,450 control chromosomes in the GnomAD database, including 751,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S267S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.84 ( 57441 hom., cov: 33)

Exomes 𝑓: 0.97 ( 693937 hom. )

Consequence

GLI2
NM_001374353.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -5.92

Publications

24 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.7370595E-7).

BP6

Variant 2-120968871-G-A is Benign according to our data. Variant chr2-120968871-G-A is described in ClinVar as Benign. ClinVar VariationId is 259736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.92 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI2	NM_001374353.1 link	c.801G>A	p.Ser267Ser	synonymous_variant	Exon 6 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.801G>A	p.Ser267Ser	synonymous_variant	Exon 6 of 14	1	NM_001374353.1	ENSP00000354586.5		A0A7I2PJA1

Frequencies

GnomAD3 genomes

AF:

0.840

AC:

127750

AN:

152102

Hom.:

57432

Cov.:

show subpopulations

Gnomad AFR

AF:

0.476

Gnomad AMI

AF:

0.997

Gnomad AMR

AF:

0.924

Gnomad ASJ

AF:

0.966

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.980

Gnomad FIN

AF:

0.996

Gnomad MID

AF:

0.930

Gnomad NFE

AF:

0.985

Gnomad OTH

AF:

0.889

GnomAD2 exomes

AF:

0.949

AC:

238228

AN:

251088

AF XY:

0.959

show subpopulations

Gnomad AFR exome

AF:

0.465

Gnomad AMR exome

AF:

0.963

Gnomad ASJ exome

AF:

0.968

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.995

Gnomad NFE exome

AF:

0.986

Gnomad OTH exome

AF:

0.962

GnomAD4 exome

AF:

0.971

AC:

1418808

AN:

1461228

Hom.:

693937

Cov.:

AF XY:

0.973

AC XY:

707184

AN XY:

726942

show subpopulations

African (AFR)

AF:

0.445

AC:

14898

AN:

33476

American (AMR)

AF:

0.959

AC:

42894

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.968

AC:

25298

AN:

26128

East Asian (EAS)

AF:

1.00

AC:

39693

AN:

39698

South Asian (SAS)

AF:

0.978

AC:

84393

AN:

86254

European-Finnish (FIN)

AF:

0.995

AC:

52695

AN:

52974

Middle Eastern (MID)

AF:

0.939

AC:

5416

AN:

5768

European-Non Finnish (NFE)

AF:

0.986

AC:

1096218

AN:

1111824

Other (OTH)

AF:

0.949

AC:

57303

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1916

3832

5749

7665

9581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21576

43152

64728

86304

107880

<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:

0.840

AC:

127800

AN:

152222

Hom.:

57441

Cov.:

AF XY:

0.845

AC XY:

62874

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.476

AC:

19754

AN:

41482

American (AMR)

AF:

0.924

AC:

14137

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.966

AC:

3353

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5151

AN:

5156

South Asian (SAS)

AF:

0.981

AC:

4728

AN:

4822

European-Finnish (FIN)

AF:

0.996

AC:

10579

AN:

10626

Middle Eastern (MID)

AF:

0.925

AC:

272

AN:

294

European-Non Finnish (NFE)

AF:

0.985

AC:

67035

AN:

68040

Other (OTH)

AF:

0.890

AC:

1882

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

661

1322

1984

2645

3306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

858

1716

2574

3432

4290

<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:

0.876

Hom.:

51528

Bravo

AF:

0.816

TwinsUK

AF:

0.988

AC:

3665

ALSPAC

AF:

0.987

AC:

3802

ESP6500AA

AF:

0.468

AC:

2064

ESP6500EA

AF:

0.984

AC:

8461

ExAC

AF:

0.940

AC:

114060

Asia WGS

AF:

0.959

AC:

3334

AN:

3478

EpiCase

AF:

0.985

EpiControl

AF:

0.985

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Holoprosencephaly 9

Benign:2

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.014

(source)

DANN

Benign

0.86

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.29

MetaRNN

Benign

7.7e-7

MetaSVM

Benign

-0.99

PhyloP100

-5.9

PROVEAN

Benign

0.91

REVEL

Benign

0.026

Sift

Benign

0.99

ClinPred

0.016

GERP RS

-9.8

Mutation Taster

=95/5

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