NM_001374353.1:c.2066C>A

Variant names:

• chr2-120986438-C-A
• rs754899023
• NM_001374353.1:c.2066C>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.2066C>A​(p.Thr689Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T689I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GLI2 NM_001374353.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.06
• 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=0.22367358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI2	NM_001374353.1	c.2066C>A	p.Thr689Asn	missense_variant	Exon 13 of 14	ENST00000361492.9	NP_001361282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI2	ENST00000361492.9	c.2066C>A	p.Thr689Asn	missense_variant	Exon 13 of 14	1	NM_001374353.1	ENSP00000354586.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461590 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

African (AFR) AF: 0.0000241 AC: 1 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.42	T;T
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.036
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N;N
PhyloP100		6.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.068
Sift	Benign	0.11	T;T
Sift4G	Uncertain	0.043	D;D
Polyphen		0.36	B;B
Vest4		0.27
MutPred		0.13		Loss of phosphorylation at T706 (P = 0.0062);Loss of phosphorylation at T706 (P = 0.0062);
MVP		0.36
MPC		0.58
ClinPred		0.63	D
GERP RS		4.7
Varity_R		0.10
gMVP		0.22
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs754899023; hg19: chr2-121744014;