2-120990247-C-T

Variant summary

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

The ENST00000361492.9(GLI2):​c.4282C>T​(p.Leu1428Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,613,696 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 10 hom., cov: 33)
Exomes 𝑓: 0.0037 ( 79 hom. )

Consequence

GLI2
ENST00000361492.9 missense

Scores

5
13

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.765
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]

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=0.005935788).
BP6
Variant 2-120990247-C-T is Benign according to our data. Variant chr2-120990247-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-120990247-C-T is described in Lovd as [Likely_benign].
BA1
GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GLI2NM_001374353.1 linkuse as main transcriptc.4282C>T p.Leu1428Phe missense_variant 14/14 ENST00000361492.9 NP_001361282.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GLI2ENST00000361492.9 linkuse as main transcriptc.4282C>T p.Leu1428Phe missense_variant 14/141 NM_001374353.1 ENSP00000354586 P2

Frequencies

GnomAD3 genomes
AF:
0.00472
AC:
719
AN:
152196
Hom.:
10
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000820
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0275
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00269
Gnomad FIN
AF:
0.00536
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00266
Gnomad OTH
AF:
0.00669
GnomAD3 exomes
AF:
0.00970
AC:
2436
AN:
251110
Hom.:
59
AF XY:
0.00776
AC XY:
1054
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.000616
Gnomad AMR exome
AF:
0.0545
Gnomad ASJ exome
AF:
0.0000993
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00225
Gnomad FIN exome
AF:
0.00638
Gnomad NFE exome
AF:
0.00245
Gnomad OTH exome
AF:
0.00898
GnomAD4 exome
AF:
0.00375
AC:
5480
AN:
1461382
Hom.:
79
Cov.:
34
AF XY:
0.00355
AC XY:
2584
AN XY:
727012
show subpopulations
Gnomad4 AFR exome
AF:
0.000538
Gnomad4 AMR exome
AF:
0.0523
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00274
Gnomad4 FIN exome
AF:
0.00735
Gnomad4 NFE exome
AF:
0.00206
Gnomad4 OTH exome
AF:
0.00328
GnomAD4 genome
AF:
0.00473
AC:
720
AN:
152314
Hom.:
10
Cov.:
33
AF XY:
0.00481
AC XY:
358
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.000818
Gnomad4 AMR
AF:
0.0275
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00269
Gnomad4 FIN
AF:
0.00536
Gnomad4 NFE
AF:
0.00266
Gnomad4 OTH
AF:
0.00662
Alfa
AF:
0.00308
Hom.:
6
Bravo
AF:
0.00770
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00234
AC:
9
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.00820
AC:
996
Asia WGS
AF:
0.00231
AC:
8
AN:
3478
EpiCase
AF:
0.00240
EpiControl
AF:
0.00101

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsOct 13, 2016- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024GLI2: BP4, BS1, BS2 -
Benign, criteria provided, single submitterclinical testingGeneDxAug 18, 2019This variant is associated with the following publications: (PMID: 29891883, 24744436) -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 10, 2014- -
Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2019- -
Holoprosencephaly 9 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine 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
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.44
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.51
D;D
Eigen
Benign
0.089
Eigen_PC
Benign
0.063
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.75
.;T
MetaRNN
Benign
0.0059
T;T
MetaSVM
Benign
-1.2
T
MutationAssessor
Uncertain
2.3
M;M
MutationTaster
Benign
0.54
D;D;D
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-2.2
N;N
REVEL
Benign
0.066
Sift
Uncertain
0.0090
D;D
Sift4G
Benign
0.10
T;T
Polyphen
0.81
P;P
Vest4
0.30
MVP
0.40
MPC
0.69
ClinPred
0.019
T
GERP RS
2.5
Varity_R
0.10
gMVP
0.14

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.

Other links and lift over

dbSNP: rs146207623; hg19: chr2-121747823; COSMIC: COSV58048330; COSMIC: COSV58048330; API