rs151090814

chr2-120990411-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001374353.1(GLI2):c.4446T>C(p.Thr1482=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,614,054 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: GLI2 NM_001374353.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.68

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-120990411-T-C is Benign according to our data. Variant chr2-120990411-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 330998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-120990411-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.68 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000972 (148/152234) while in subpopulation AFR AF= 0.00308 (128/41542). AF 95% confidence interval is 0.00265. There are 1 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 148 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI2	NM_001374353.1	c.4446T>C	p.Thr1482=	synonymous_variant	14/14	ENST00000361492.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI2	ENST00000361492.9	c.4446T>C	p.Thr1482=	synonymous_variant	14/14	1	NM_001374353.1	P2

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 148 AN: 152116 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000370 AC: 93 AN: 251300 Hom.: 0 AF XY: 0.000294 AC XY: 40 AN XY: 135844

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000159 AC: 232 AN: 1461820 Hom.: 0 Cov.: 34 AF XY: 0.000161 AC XY: 117 AN XY: 727214

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000656

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000972 AC: 148 AN: 152234 Hom.: 1 Cov.: 33 AF XY: 0.000994 AC XY: 74 AN XY: 74436

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000556 Hom.: 0

Bravo AF: 0.00104

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 15, 2016

- -

Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Holoprosencephaly 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

GLI2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 10, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.048
Dann	Benign	0.50

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: rs151090814; hg19: chr2-121747987;