chr2-120990472-G-A

Variant names:

• chr2-120990472-G-A
• rs114814747
• NM_001374353.1:c.4507G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374353.1(GLI2):​c.4507G>A​(p.Asp1503Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,798 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1503E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0094 (16 hom., cov: 32)
  • Exomes 𝑓: 0.013 (137 hom.)
• Consequence: GLI2 NM_001374353.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:12
• Conservation: PhyloP100: 10.0
• Publications: 17 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=0.008831322).
• BP6: Variant 2-120990472-G-A is Benign according to our data. Variant chr2-120990472-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 37084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00944 (1434/151976) while in subpopulation NFE AF = 0.0144 (978/67928). AF 95% confidence interval is 0.0136. There are 16 homozygotes in GnomAd4. There are 687 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AD,AR gene

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.4507G>A	p.Asp1503Asn	missense	Exon 14 of 14	NP_001361282.1	A0A7I2PJA1
	GLI2	NM_001371271.1		c.4558G>A	p.Asp1520Asn	missense	Exon 14 of 14	NP_001358200.1	P10070-5
	GLI2	NM_005270.5		c.4558G>A	p.Asp1520Asn	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.4507G>A	p.Asp1503Asn	missense	Exon 14 of 14	ENSP00000354586.5	A0A7I2PJA1
	GLI2	ENST00000452319.6	TSL:5	c.4558G>A	p.Asp1520Asn	missense	Exon 13 of 13	ENSP00000390436.1	P10070-5
	GLI2	ENST00000934404.1		c.4501G>A	p.Asp1501Asn	missense	Exon 14 of 14	ENSP00000604463.1

Frequencies

GnomAD3 genomes AF: 0.00945 AC: 1435 AN: 151858 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00264

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.00662

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00960

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.00674

GnomAD2 exomes AF: 0.00935 AC: 2349 AN: 251144 AF XY: 0.00977

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.00972

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00249

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.00961

GnomAD4 exome AF: 0.0128 AC: 18678 AN: 1461822 Hom.: 137 Cov.: 34 AF XY: 0.0128 AC XY: 9287 AN XY: 727210

African (AFR) AF: 0.00236 AC: 79 AN: 33478

American (AMR) AF: 0.00364 AC: 163 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 271 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0117 AC: 1007 AN: 86256

European-Finnish (FIN) AF: 0.00358 AC: 191 AN: 53404

Middle Eastern (MID) AF: 0.00589 AC: 34 AN: 5768

European-Non Finnish (NFE) AF: 0.0146 AC: 16282 AN: 1111962

Other (OTH) AF: 0.0108 AC: 650 AN: 60394

GnomAD4 genome AF: 0.00944 AC: 1434 AN: 151976 Hom.: 16 Cov.: 32 AF XY: 0.00925 AC XY: 687 AN XY: 74298

African (AFR) AF: 0.00263 AC: 109 AN: 41466

American (AMR) AF: 0.00655 AC: 100 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00961 AC: 46 AN: 4788

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10590

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0144 AC: 978 AN: 67928

Other (OTH) AF: 0.00667 AC: 14 AN: 2100

Alfa AF: 0.0123 Hom.: 34

Bravo AF: 0.00910

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0144 AC: 124

ExAC AF: 0.0100 AC: 1220

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0130

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
1	-	2	Holoprosencephaly 9 (3)
-	-	2	not specified (2)
-	-	1	Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (1)
-	-	1	Partial androgen insensitivity syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		10
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.43
MPC		0.60
ClinPred		0.026	T
GERP RS		5.0
Varity_R		0.66
gMVP		0.36
Mutation Taster		=29/71	disease causing

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: rs114814747; hg19: chr2-121748048;