rs12711538

Variant names:

• chr2-120989830-G-A
• rs12711538
• NM_001374353.1:c.3865G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374353.1(GLI2):​c.3865G>A​(p.Asp1289Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 1,611,070 control chromosomes in the GnomAD database, including 391,822 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33527 hom., cov: 35)
  • Exomes 𝑓: 0.70 (358295 hom.)
• Consequence: GLI2 NM_001374353.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.13
• Publications: 43 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.033025E-6).
• BP6: Variant 2-120989830-G-A is Benign according to our data. Variant chr2-120989830-G-A is described in ClinVar as Benign. ClinVar VariationId is 95272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

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.3865G>A	p.Asp1289Asn	missense	Exon 14 of 14	NP_001361282.1	A0A7I2PJA1
	GLI2	NM_001371271.1		c.3916G>A	p.Asp1306Asn	missense	Exon 14 of 14	NP_001358200.1	P10070-5
	GLI2	NM_005270.5		c.3916G>A	p.Asp1306Asn	missense	Exon 14 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.3865G>A	p.Asp1289Asn	missense	Exon 14 of 14	ENSP00000354586.5	A0A7I2PJA1
	GLI2	ENST00000452319.6	TSL:5	c.3916G>A	p.Asp1306Asn	missense	Exon 13 of 13	ENSP00000390436.1	P10070-5
	GLI2	ENST00000934404.1		c.3859G>A	p.Asp1287Asn	missense	Exon 14 of 14	ENSP00000604463.1

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100139 AN: 152032 Hom.: 33512 Cov.: 35

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.668

GnomAD2 exomes AF: 0.645 AC: 159215 AN: 246908 AF XY: 0.646

Gnomad AFR exome AF: 0.577

Gnomad AMR exome AF: 0.580

Gnomad ASJ exome AF: 0.671

Gnomad EAS exome AF: 0.464

Gnomad FIN exome AF: 0.676

Gnomad NFE exome AF: 0.727

Gnomad OTH exome AF: 0.671

GnomAD4 exome AF: 0.697 AC: 1016406 AN: 1458920 Hom.: 358295 Cov.: 57 AF XY: 0.692 AC XY: 502381 AN XY: 725534

African (AFR) AF: 0.574 AC: 19197 AN: 33448

American (AMR) AF: 0.585 AC: 26079 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 17631 AN: 26046

East Asian (EAS) AF: 0.474 AC: 18800 AN: 39656

South Asian (SAS) AF: 0.526 AC: 45297 AN: 86064

European-Finnish (FIN) AF: 0.673 AC: 35253 AN: 52356

Middle Eastern (MID) AF: 0.636 AC: 3666 AN: 5768

European-Non Finnish (NFE) AF: 0.729 AC: 809840 AN: 1110754

Other (OTH) AF: 0.675 AC: 40643 AN: 60250

GnomAD4 genome AF: 0.658 AC: 100174 AN: 152150 Hom.: 33527 Cov.: 35 AF XY: 0.652 AC XY: 48522 AN XY: 74378

African (AFR) AF: 0.580 AC: 24099 AN: 41522

American (AMR) AF: 0.646 AC: 9887 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2363 AN: 3470

East Asian (EAS) AF: 0.476 AC: 2459 AN: 5164

South Asian (SAS) AF: 0.504 AC: 2431 AN: 4822

European-Finnish (FIN) AF: 0.661 AC: 7004 AN: 10594

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.730 AC: 49583 AN: 67966

Other (OTH) AF: 0.670 AC: 1412 AN: 2108

Alfa AF: 0.702 Hom.: 59648

Bravo AF: 0.653

TwinsUK AF: 0.718 AC: 2661

ALSPAC AF: 0.723 AC: 2787

ESP6500AA AF: 0.576 AC: 2536

ESP6500EA AF: 0.728 AC: 6262

ExAC AF: 0.644 AC: 78079

Asia WGS AF: 0.499 AC: 1736 AN: 3478

EpiCase AF: 0.735

EpiControl AF: 0.735

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Holoprosencephaly 9 (2)
-	-	1	Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (1)
-	-	1	Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.9
DANN	Benign	0.25
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0000020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
PhyloP100		2.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.081
Sift	Benign	1.0	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.011
MPC		0.32
ClinPred		0.00087	T
GERP RS		2.1
Varity_R		0.039
gMVP		0.047
Mutation Taster		=100/0	polymorphism (auto)

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: rs12711538; hg19: chr2-121747406; COSMIC: COSV58041761; COSMIC: COSV58041761;