2-120988962-C-A

Variant names:

• chr2-120988962-C-A
• rs140479803
• NM_001374353.1:c.2997C>A

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.2997C>A​(p.Asp999Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D999N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GLI2 NM_001374353.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.81
• Publications: 4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, Ambry Genetics
• 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=0.07170066).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI2	NM_001374353.1	MANE Select	c.2997C>A	p.Asp999Glu	missense	Exon 14 of 14	NP_001361282.1
	GLI2	NM_001371271.1		c.3048C>A	p.Asp1016Glu	missense	Exon 14 of 14	NP_001358200.1
	GLI2	NM_005270.5		c.3048C>A	p.Asp1016Glu	missense	Exon 14 of 14	NP_005261.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI2	ENST00000361492.9	TSL:1 MANE Select	c.2997C>A	p.Asp999Glu	missense	Exon 14 of 14	ENSP00000354586.5
	GLI2	ENST00000452319.6	TSL:5	c.3048C>A	p.Asp1016Glu	missense	Exon 13 of 13	ENSP00000390436.1
	GLI2	ENST00000341310.10	TSL:2	n.*2096C>A		non_coding_transcript_exon	Exon 10 of 10	ENSP00000344473.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.015
DANN	Benign	0.76
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.77	N
PhyloP100		-3.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.045
Sift	Benign	0.41	T
Sift4G	Benign	0.59	T
Polyphen		0.017	B
Vest4		0.045
MutPred		0.20		Gain of solvent accessibility (P = 0.0306)
MVP		0.18
MPC		0.31
ClinPred		0.11	T
GERP RS		-4.9
Varity_R		0.046
gMVP		0.52
Mutation Taster		=94/6	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: rs140479803; hg19: chr2-121746538;