rs142793481

Positions:

chr2-120968790-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001374353.1(GLI2):c.720C>T(p.Asp240=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,613,764 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0064 ( 53 hom. )

Consequence

GLI2
NM_001374353.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.885

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040371716).

BP6

Variant 2-120968790-C-T is Benign according to our data. Variant chr2-120968790-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-120968790-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.885 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00497 (757/152372) while in subpopulation SAS AF= 0.00745 (36/4830). AF 95% confidence interval is 0.00553. There are 1 homozygotes in gnomad4. There are 462 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 757 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLI2	NM_001374353.1 linkuse as main transcript	c.720C>T	p.Asp240=	synonymous_variant	6/14	ENST00000361492.9	NP_001361282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLI2	ENST00000361492.9 linkuse as main transcript	c.720C>T	p.Asp240=	synonymous_variant	6/14	1	NM_001374353.1	ENSP00000354586	P2

Frequencies

GnomAD3 genomes

AF:

0.00497

AC:

757

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.00765

Gnomad FIN

AF:

0.0233

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00498

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00729

AC:

1833

AN:

251292

Hom.:

AF XY:

0.00737

AC XY:

1001

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.000801

Gnomad AMR exome

AF:

0.0107

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00245

Gnomad SAS exome

AF:

0.00751

Gnomad FIN exome

AF:

0.0214

Gnomad NFE exome

AF:

0.00575

Gnomad OTH exome

AF:

0.00865

GnomAD4 exome

AF:

0.00643

AC:

9391

AN:

1461392

Hom.:

Cov.:

AF XY:

0.00643

AC XY:

4674

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00957

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.00224

Gnomad4 SAS exome

AF:

0.00843

Gnomad4 FIN exome

AF:

0.0210

Gnomad4 NFE exome

AF:

0.00589

Gnomad4 OTH exome

AF:

0.00634

GnomAD4 genome

AF:

0.00497

AC:

757

AN:

152372

Hom.:

Cov.:

AF XY:

0.00620

AC XY:

462

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.00359

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00290

Gnomad4 SAS

AF:

0.00745

Gnomad4 FIN

AF:

0.0233

Gnomad4 NFE

AF:

0.00498

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00509

Hom.:

Bravo

AF:

0.00368

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.00731

AC:

888

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00523

EpiControl

AF:

0.00456

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 17, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	GLI2: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2021	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Holoprosencephaly 9

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Benign

3.2

DANN

Uncertain

0.99

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

D;D;D

PROVEAN

Benign

-1.6

REVEL

Benign

0.16

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.049

MVP

0.40

ClinPred

0.023

GERP RS

-4.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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