dbSNP rs17005499: GLI2:c.457+420G>A (chr2-120951865-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001374353.1(GLI2):c.457+420G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0978 in 158,576 control chromosomes in the GnomAD database, including 2,505 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.10 ( 2486 hom., cov: 33)

Exomes 𝑓: 0.021 ( 19 hom. )

Consequence

GLI2
NM_001374353.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.473

Publications

2 publications found

Variant links:

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

GLI2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.34 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GLI2	NM_001374353.1	MANE Select	c.457+420G>A	intron	N/A	NP_001361282.1
GLI2	NM_001371271.1		c.457+420G>A	intron	N/A	NP_001358200.1
GLI2	NM_005270.5		c.457+420G>A	intron	N/A	NP_005261.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GLI2	ENST00000361492.9	TSL:1 MANE Select	c.457+420G>A	intron	N/A	ENSP00000354586.5
GLI2	ENST00000360874.10	TSL:1	n.231-16849G>A	intron	N/A
GLI2	ENST00000433812.1	TSL:1	n.*156+420G>A	intron	N/A	ENSP00000402383.1

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15330

AN:

152002

Hom.:

2480

Cov.:

show subpopulations

Gnomad AFR

AF:

0.345

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0422

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00247

Gnomad OTH

AF:

0.0651

GnomAD4 exome

AF:

0.0208

AC:

134

AN:

6456

Hom.:

AF XY:

0.0184

AC XY:

AN XY:

3308

show subpopulations

African (AFR)

AF:

0.312

AC:

AN:

266

American (AMR)

AF:

0.0294

AC:

AN:

170

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

AN:

270

East Asian (EAS)

AF:

0.00

AC:

AN:

310

South Asian (SAS)

AF:

0.0385

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

306

Middle Eastern (MID)

AF:

0.0588

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00349

AC:

AN:

4580

Other (OTH)

AF:

0.0498

AC:

AN:

442

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.101

AC:

15372

AN:

152120

Hom.:

2486

Cov.:

AF XY:

0.0976

AC XY:

7257

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.345

AC:

14288

AN:

41438

American (AMR)

AF:

0.0422

AC:

645

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.0118

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00248

AC:

169

AN:

68008

Other (OTH)

AF:

0.0645

AC:

136

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

512

1024

1537

2049

2561

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0855

Hom.:

234

Bravo

AF:

0.116

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.61

(source)

DANN

Benign

0.45

PhyloP100

-0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over