2-120797351-G-C

Variant names:

• chr2-120797351-G-C
• rs574656730
• NM_001374353.1:c.31G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001374353.1(GLI2):​c.31G>C​(p.Glu11Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E11K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GLI2 NM_001374353.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.13
• Publications: 0 publications found

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]

GLI2 Gene-Disease associations (from GenCC):

• holoprosencephaly 9

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Illumina
• combined pituitary hormone deficiencies, genetic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26112467).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374353.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI2	NM_001374353.1	MANE Select	c.31G>C	p.Glu11Gln	missense	Exon 2 of 14	NP_001361282.1	A0A7I2PJA1
	GLI2	NM_001371271.1		c.31G>C	p.Glu11Gln	missense	Exon 2 of 14	NP_001358200.1	P10070-5
	GLI2	NM_005270.5		c.31G>C	p.Glu11Gln	missense	Exon 2 of 14	NP_005261.2	P10070-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI2	ENST00000361492.9	TSL:1 MANE Select	c.31G>C	p.Glu11Gln	missense	Exon 2 of 14	ENSP00000354586.5	A0A7I2PJA1
	GLI2	ENST00000418323.6	TSL:1	c.31G>C	p.Glu11Gln	missense	Exon 2 of 3	ENSP00000398992.1	Q1PSW9
	GLI2	ENST00000360874.10	TSL:1	n.7G>C		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	GLI2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.18
Sift	Benign	0.12	T
Sift4G	Benign	0.19	T
Polyphen		0.59	P
Vest4		0.20
MutPred		0.069		Loss of solvent accessibility (P = 0.0721)
MVP		0.56
MPC		0.68
ClinPred		0.75	D
GERP RS		5.9
PromoterAI		0.016	Neutral
Varity_R		0.12
gMVP		0.26
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs574656730; hg19: chr2-121554927;