rs61732852

chr2-120984548-G-Achr2-120984548-G-T

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.1710G>A(p.Thr570=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,196 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (13 hom., cov: 33)
  • Exomes 𝑓: 0.012 (129 hom.)
• Consequence: GLI2 NM_001374353.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -7.06

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=-0.7).
• BP6: Variant 2-120984548-G-A is Benign according to our data. Variant chr2-120984548-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-120984548-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-7.06 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0105 (1595/152314) while in subpopulation NFE AF= 0.0147 (1002/68026). AF 95% confidence interval is 0.014. There are 13 homozygotes in gnomad4. There are 791 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1597 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI2	NM_001374353.1	c.1710G>A	p.Thr570=	synonymous_variant	12/14	ENST00000361492.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI2	ENST00000361492.9	c.1710G>A	p.Thr570=	synonymous_variant	12/14	1	NM_001374353.1	P2

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1597 AN: 152196 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0117 AC: 2953 AN: 251452 Hom.: 25 AF XY: 0.0122 AC XY: 1662 AN XY: 135898

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.0224

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00660

Gnomad FIN exome AF: 0.0239

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.0124 AC: 18105 AN: 1461882 Hom.: 129 Cov.: 33 AF XY: 0.0124 AC XY: 8985 AN XY: 727242

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00541

Gnomad4 ASJ exome AF: 0.0233

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00620

Gnomad4 FIN exome AF: 0.0235

Gnomad4 NFE exome AF: 0.0132

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.0105 AC: 1595 AN: 152314 Hom.: 13 Cov.: 33 AF XY: 0.0106 AC XY: 791 AN XY: 74480

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0238

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0108 Hom.: 8

Bravo AF: 0.00869

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0164

EpiControl AF: 0.0132

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	GLI2: BP4, BP7, BS1, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 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_noAF	Benign	-0.70
Cadd	Benign	0.052
Dann	Benign	0.80

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: rs61732852; hg19: chr2-121742124;