NM_001374353.1:c.4281G>A

Variant names:

• chr2-120990246-G-A
• rs146467786
• NM_001374353.1:c.4281G>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.4281G>A​(p.Met1427Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,613,706 control chromosomes in the GnomAD database, including 89 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (79 hom.)
• Consequence: GLI2 NM_001374353.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.35
• Publications: 10 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=0.002585888).
• BP6: Variant 2-120990246-G-A is Benign according to our data. Variant chr2-120990246-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0505 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.4281G>A	p.Met1427Ile	missense	Exon 14 of 14	NP_001361282.1	A0A7I2PJA1
	GLI2	NM_001371271.1		c.4332G>A	p.Met1444Ile	missense	Exon 14 of 14	NP_001358200.1	P10070-5
	GLI2	NM_005270.5		c.4332G>A	p.Met1444Ile	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.4281G>A	p.Met1427Ile	missense	Exon 14 of 14	ENSP00000354586.5	A0A7I2PJA1
	GLI2	ENST00000452319.6	TSL:5	c.4332G>A	p.Met1444Ile	missense	Exon 13 of 13	ENSP00000390436.1	P10070-5
	GLI2	ENST00000934404.1		c.4275G>A	p.Met1425Ile	missense	Exon 14 of 14	ENSP00000604463.1

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 719 AN: 152200 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00970 AC: 2435 AN: 251078 AF XY: 0.00775

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.0545

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00633

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00898

GnomAD4 exome AF: 0.00375 AC: 5478 AN: 1461388 Hom.: 79 Cov.: 34 AF XY: 0.00355 AC XY: 2583 AN XY: 727020

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.0523 AC: 2337 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00274 AC: 236 AN: 86258

European-Finnish (FIN) AF: 0.00733 AC: 388 AN: 52926

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00206 AC: 2291 AN: 1112006

Other (OTH) AF: 0.00328 AC: 198 AN: 60390

GnomAD4 genome AF: 0.00473 AC: 720 AN: 152318 Hom.: 10 Cov.: 33 AF XY: 0.00481 AC XY: 358 AN XY: 74474

African (AFR) AF: 0.000818 AC: 34 AN: 41582

American (AMR) AF: 0.0275 AC: 421 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4832

European-Finnish (FIN) AF: 0.00537 AC: 57 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00266 AC: 181 AN: 68014

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.000967 Hom.: 3

Bravo AF: 0.00770

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00820 AC: 996

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Holoprosencephaly 9 (2)
-	-	2	Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.032
Sift	Benign	0.048	D
Sift4G	Benign	0.42	T
Polyphen		0.013	B
Vest4		0.23
MutPred		0.29		Loss of catalytic residue at M1444 (P = 0.018)
MVP		0.33
MPC		0.36
ClinPred		0.0031	T
GERP RS		3.7
Varity_R		0.13
gMVP		0.12
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: rs146467786; hg19: chr2-121747822; COSMIC: COSV58048319;