rs142793481

chr2-120968790-C-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.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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.885

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 (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 GnomAd at 757 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 757 AN: 152254 Hom.: 1 Cov.: 33

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.: 20 AF XY: 0.00737 AC XY: 1001 AN XY: 135884

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.: 53 Cov.: 34 AF XY: 0.00643 AC XY: 4674 AN XY: 727046

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.: 1 Cov.: 33 AF XY: 0.00620 AC XY: 462 AN XY: 74498

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.: 2

Bravo AF: 0.00368

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00731 AC: 888

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00456

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

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:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2021	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	GLI2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 20, 2020	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

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	T
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	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.049	D
MVP		0.40
ClinPred		0.023	T
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

Other links and lift over

dbSNP: rs142793481; hg19: chr2-121726366; COSMIC: COSV58047232;