rs146467786

chr2-120990246-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374353.1(GLI2):c.4281G>A(p.Met1427Ile) 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 1,613,706 control chromosomes in the GnomAD database, including 89 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (79 hom.)
• Consequence: GLI2 NM_001374353.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.35

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002585888).
• BP6: Variant 2-120990246-G-A is Benign according to our data. Variant chr2-120990246-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 194230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-120990246-G-A 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	UniProt
GLI2	NM_001374353.1	c.4281G>A	p.Met1427Ile	missense_variant	14/14	ENST00000361492.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI2	ENST00000361492.9	c.4281G>A	p.Met1427Ile	missense_variant	14/14	1	NM_001374353.1	P2

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 719 AN: 152200 Hom.: 10 Cov.: 33

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: 0.00537

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00970 AC: 2435 AN: 251078 Hom.: 59 AF XY: 0.00775 AC XY: 1053 AN XY: 135804

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: 0.00633

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00898

GnomAD4 exome AF: 0.00375 AC: 5478 AN: 1461388 Hom.: 79 Cov.: 34 AF XY: 0.00355 AC XY: 2583 AN XY: 727020

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: 0.00733

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.00473 AC: 720 AN: 152318 Hom.: 10 Cov.: 33 AF XY: 0.00481 AC XY: 358 AN XY: 74474

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: 0.00537

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00110 Hom.: 3

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 13, 2016	- -
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	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	GLI2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2018	This variant is associated with the following publications: (PMID: 27535533, 17096318, 22967285) -

Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 09, 2021	- -

Holoprosencephaly 9 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). 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. -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Met1444Ile variant, sometimes called p.Met1116Ile due to a difference in cDNA numbering, in GLI2 has been identified in an individual with possible holoprosencephaly and 4 individuals with combined pituitary hormone deficiency but not holoprosencephaly (PMID: 17096318, 22967285). This variant has also been identified in >6% of Latino chromosomes and 20 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant holoprosencephaly with heminasal aplasia and orbital anomalies. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 10, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	15
Dann	Benign	0.96
DEOGEN2	Uncertain	0.44	T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.91	D
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.032
Sift	Benign	0.048	D;D
Sift4G	Benign	0.42	T;T
Polyphen		0.013	B;B
Vest4		0.23
MutPred		0.29		Loss of catalytic residue at M1444 (P = 0.018);Loss of catalytic residue at M1444 (P = 0.018);
MVP		0.33
MPC		0.36
ClinPred		0.0031	T
GERP RS		3.7
Varity_R		0.13
gMVP		0.12

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

Other links and lift over

dbSNP: rs146467786; hg19: chr2-121747822; COSMIC: COSV58048319; COSMIC: COSV58048319;