rs149140724

chr2-120989968-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374353.1(GLI2):c.4003A>G(p.Met1335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,611,040 control chromosomes in the GnomAD database, including 152 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 0.0094 (17 hom., cov: 33)
  • Exomes 𝑓: 0.013 (135 hom.)
• Consequence: GLI2 NM_001374353.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0870

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=0.0018228292).
• BP6: Variant 2-120989968-A-G is Benign according to our data. Variant chr2-120989968-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 194231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-120989968-A-G is described in Lovd as [Likely_benign]. Variant chr2-120989968-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00939 (1430/152268) while in subpopulation NFE AF= 0.0146 (990/67984). AF 95% confidence interval is 0.0138. There are 17 homozygotes in gnomad4. There are 683 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1431 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI2	NM_001374353.1	c.4003A>G	p.Met1335Val	missense_variant	14/14	ENST00000361492.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI2	ENST00000361492.9	c.4003A>G	p.Met1335Val	missense_variant	14/14	1	NM_001374353.1	P2

Frequencies

GnomAD3 genomes AF: 0.00941 AC: 1431 AN: 152152 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00864 AC: 2080 AN: 240838 Hom.: 11 AF XY: 0.00887 AC XY: 1169 AN XY: 131776

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.00989

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00491

Gnomad FIN exome AF: 0.00256

Gnomad NFE exome AF: 0.0147

Gnomad OTH exome AF: 0.00930

GnomAD4 exome AF: 0.0125 AC: 18252 AN: 1458772 Hom.: 135 Cov.: 34 AF XY: 0.0124 AC XY: 8960 AN XY: 725496

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.00370

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00533

Gnomad4 FIN exome AF: 0.00365

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.00939 AC: 1430 AN: 152268 Hom.: 17 Cov.: 33 AF XY: 0.00917 AC XY: 683 AN XY: 74462

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.00666

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00581

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.0126 Hom.: 10

Bravo AF: 0.00916

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00434 AC: 19

ESP6500EA AF: 0.0139 AC: 119

ExAC AF: 0.00918 AC: 1112

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0130

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	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	GLI2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2020	This variant is associated with the following publications: (PMID: 29165578, 24744436) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	3.1
Dann	Benign	0.65
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.74	D
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.77	N;N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.057
Sift	Benign	0.13	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.089
MVP		0.23
MPC		0.33
ClinPred		0.00088	T
GERP RS		-5.3
Varity_R		0.091
gMVP		0.16

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: rs149140724; hg19: chr2-121747544;