rs146811565

Variant names:

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.2889C>T(p.Ser963Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00812 in 1,490,924 control chromosomes in the GnomAD database, including 853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.044 ( 510 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 343 hom. )

Consequence

GLI2
NM_001374353.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.78

Publications

3 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 (BayesDel_noAF=-0.85).

BP6

Variant 2-120988854-C-T is Benign according to our data. Variant chr2-120988854-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.78 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI2	NM_001374353.1 link	c.2889C>T	p.Ser963Ser	synonymous_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.2889C>T	p.Ser963Ser	synonymous_variant	Exon 14 of 14	1	NM_001374353.1	ENSP00000354586.5		A0A7I2PJA1

Frequencies

GnomAD3 genomes

AF:

0.0435

AC:

6584

AN:

151214

Hom.:

510

Cov.:

show subpopulations

Gnomad AFR

AF:

0.150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0162

Gnomad ASJ

AF:

0.00754

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000532

Gnomad OTH

AF:

0.0284

GnomAD2 exomes

AF:

0.00561

AC:

630

AN:

112308

AF XY:

0.00434

show subpopulations

Gnomad AFR exome

AF:

0.146

Gnomad AMR exome

AF:

0.00702

Gnomad ASJ exome

AF:

0.00520

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000432

Gnomad OTH exome

AF:

0.00575

GnomAD4 exome

AF:

0.00411

AC:

5509

AN:

1339606

Hom.:

343

Cov.:

AF XY:

0.00362

AC XY:

2392

AN XY:

661220

show subpopulations

African (AFR)

AF:

0.154

AC:

4229

AN:

27464

American (AMR)

AF:

0.00824

AC:

274

AN:

33240

Ashkenazi Jewish (ASJ)

AF:

0.00650

AC:

150

AN:

23060

East Asian (EAS)

AF:

0.0000650

AC:

AN:

30748

South Asian (SAS)

AF:

0.000350

AC:

AN:

77244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32960

Middle Eastern (MID)

AF:

0.00575

AC:

AN:

5040

European-Non Finnish (NFE)

AF:

0.000220

AC:

232

AN:

1054996

Other (OTH)

AF:

0.0103

AC:

566

AN:

54854

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

267

534

801

1068

1335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<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:

0.0436

AC:

6592

AN:

151318

Hom.:

510

Cov.:

AF XY:

0.0418

AC XY:

3088

AN XY:

73956

show subpopulations

African (AFR)

AF:

0.150

AC:

6220

AN:

41454

American (AMR)

AF:

0.0162

AC:

246

AN:

15184

Ashkenazi Jewish (ASJ)

AF:

0.00754

AC:

AN:

3448

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10262

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000532

AC:

AN:

67650

Other (OTH)

AF:

0.0281

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

298

596

895

1193

1491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0259

Hom.:

Asia WGS

AF:

0.0140

AC:

AN:

3204

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 18, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Oct 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Holoprosencephaly 9

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.52

(source)

DANN

Benign

0.78

PhyloP100

-1.8

Mutation Taster

=99/1

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