rs12711538

chr2-120989830-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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:10

Conservation

PhyloP100: 2.13

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 95272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-120989830-G-A is described in Lovd as [Benign].

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/exons	MANE	UniProt
GLI2	NM_001374353.1 linkuse as main transcript	c.3865G>A	p.Asp1289Asn	missense_variant	14/14	ENST00000361492.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI2	ENST00000361492.9 linkuse as main transcript	c.3865G>A	p.Asp1289Asn	missense_variant	14/14	1	NM_001374353.1	P2

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

GnomAD3 exomes

AF:

0.645

AC:

159215

AN:

246908

Hom.:

52450

AF XY:

0.646

AC XY:

86616

AN XY:

134112

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 SAS exome

AF:

0.525

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

Gnomad4 AFR exome

AF:

0.574

Gnomad4 AMR exome

AF:

0.585

Gnomad4 ASJ exome

AF:

0.677

Gnomad4 EAS exome

AF:

0.474

Gnomad4 SAS exome

AF:

0.526

Gnomad4 FIN exome

AF:

0.673

Gnomad4 NFE exome

AF:

0.729

Gnomad4 OTH exome

AF:

0.675

GnomAD4 genome

AF:

0.658

AC:

100174

AN:

152150

Hom.:

33527

Cov.:

AF XY:

0.652

AC XY:

48522

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.580

Gnomad4 AMR

AF:

0.646

Gnomad4 ASJ

AF:

0.681

Gnomad4 EAS

AF:

0.476

Gnomad4 SAS

AF:

0.504

Gnomad4 FIN

AF:

0.661

Gnomad4 NFE

AF:

0.730

Gnomad4 OTH

AF:

0.670

Alfa

AF:

0.709

Hom.:

40383

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	- -

Holoprosencephaly 9

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

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

Dann

Benign

0.25

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0039

MetaRNN

Benign

0.0000020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.5

N;N

MutationTaster

Benign

1.0

P;P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over