2-120989380-G-T

Position:

chr2-120989380-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001374353.1(GLI2):c.3415G>T(p.Ala1139Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 1,612,702 control chromosomes in the GnomAD database, including 384,436 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1139V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.61 ( 29634 hom., cov: 35)

Exomes 𝑓: 0.69 ( 354802 hom. )

Consequence

GLI2
NM_001374353.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.106

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=2.11276E-6).

BP6

Variant 2-120989380-G-T is Benign according to our data. Variant chr2-120989380-G-T is described in ClinVar as [Benign]. Clinvar id is 95271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-120989380-G-T 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.3415G>T	p.Ala1139Ser	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.3415G>T	p.Ala1139Ser	missense_variant	14/14	1	NM_001374353.1	P2

Frequencies

GnomAD3 genomes

AF:

0.608

AC:

92417

AN:

152030

Hom.:

29626

Cov.:

show subpopulations

Gnomad AFR

AF:

0.405

Gnomad AMI

AF:

0.802

Gnomad AMR

AF:

0.627

Gnomad ASJ

AF:

0.674

Gnomad EAS

AF:

0.477

Gnomad SAS

AF:

0.501

Gnomad FIN

AF:

0.661

Gnomad MID

AF:

0.684

Gnomad NFE

AF:

0.729

Gnomad OTH

AF:

0.634

GnomAD3 exomes

AF:

0.632

AC:

156066

AN:

247018

Hom.:

50935

AF XY:

0.636

AC XY:

85607

AN XY:

134598

show subpopulations

Gnomad AFR exome

AF:

0.394

Gnomad AMR exome

AF:

0.572

Gnomad ASJ exome

AF:

0.667

Gnomad EAS exome

AF:

0.464

Gnomad SAS exome

AF:

0.519

Gnomad FIN exome

AF:

0.677

Gnomad NFE exome

AF:

0.728

Gnomad OTH exome

AF:

0.666

GnomAD4 exome

AF:

0.691

AC:

1009779

AN:

1460554

Hom.:

354802

Cov.:

AF XY:

0.688

AC XY:

499644

AN XY:

726614

show subpopulations

Gnomad4 AFR exome

AF:

0.392

Gnomad4 AMR exome

AF:

0.575

Gnomad4 ASJ exome

AF:

0.671

Gnomad4 EAS exome

AF:

0.474

Gnomad4 SAS exome

AF:

0.521

Gnomad4 FIN exome

AF:

0.674

Gnomad4 NFE exome

AF:

0.729

Gnomad4 OTH exome

AF:

0.661

GnomAD4 genome

AF:

0.608

AC:

92433

AN:

152148

Hom.:

29634

Cov.:

AF XY:

0.603

AC XY:

44882

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.404

Gnomad4 AMR

AF:

0.627

Gnomad4 ASJ

AF:

0.674

Gnomad4 EAS

AF:

0.476

Gnomad4 SAS

AF:

0.501

Gnomad4 FIN

AF:

0.661

Gnomad4 NFE

AF:

0.730

Gnomad4 OTH

AF:

0.636

Alfa

AF:

0.705

Hom.:

64819

Bravo

AF:

0.594

TwinsUK

AF:

0.718

AC:

2661

ALSPAC

AF:

0.723

AC:

2787

ESP6500AA

AF:

0.413

AC:

1801

ESP6500EA

AF:

0.731

AC:

6231

ExAC

AF:

0.627

AC:

75614

Asia WGS

AF:

0.482

AC:

1677

AN:

3478

EpiCase

AF:

0.734

EpiControl

AF:

0.736

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2013	- -

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 28, 2018

- -

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

0.069

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.15

DANN

Benign

0.79

DEOGEN2

Benign

0.29

T;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.61

.;T

MetaRNN

Benign

0.0000021

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.66

N;N

REVEL

Benign

0.019

Sift

Benign

0.52

T;T

Sift4G

Benign

0.60

T;T

Polyphen

0.16

B;B

Vest4

0.010

MPC

0.34

ClinPred

0.0042

GERP RS

0.039

Varity_R

0.051

gMVP

0.017

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