dbSNP rs112131051: GLI2:c.-7G>A (chr2-120797314-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001374353.1(GLI2):c.-7G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,613,870 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 15 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 11 hom. )

Consequence

GLI2
NM_001374353.1 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.36

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 2-120797314-G-A is Benign according to our data. Variant chr2-120797314-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00811 (1234/152174) while in subpopulation AFR AF = 0.027 (1120/41526). AF 95% confidence interval is 0.0257. There are 15 homozygotes in GnomAd4. There are 581 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GLI2	NM_001374353.1	MANE Select	c.-7G>A	5_prime_UTR	Exon 2 of 14	NP_001361282.1
GLI2	NM_001371271.1		c.-7G>A	5_prime_UTR	Exon 2 of 14	NP_001358200.1
GLI2	NM_005270.5		c.-7G>A	5_prime_UTR	Exon 2 of 14	NP_005261.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GLI2	ENST00000361492.9	TSL:1 MANE Select	c.-7G>A	5_prime_UTR	Exon 2 of 14	ENSP00000354586.5
GLI2	ENST00000418323.6	TSL:1	c.-7G>A	5_prime_UTR	Exon 2 of 3	ENSP00000398992.1
GLI2	ENST00000934404.1		c.-7G>A	5_prime_UTR	Exon 2 of 14	ENSP00000604463.1

Frequencies

GnomAD3 genomes

AF:

0.00810

AC:

1232

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00609

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:

0.000162

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00221

AC:

554

AN:

251114

AF XY:

0.00147

show subpopulations

Gnomad AFR exome

AF:

0.0288

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000841

AC:

1230

AN:

1461696

Hom.:

Cov.:

AF XY:

0.000721

AC XY:

524

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.0277

AC:

926

AN:

33474

American (AMR)

AF:

0.00188

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000151

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000737

AC:

AN:

1111882

Other (OTH)

AF:

0.00190

AC:

115

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

134

202

269

336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00811

AC:

1234

AN:

152174

Hom.:

Cov.:

AF XY:

0.00781

AC XY:

581

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0270

AC:

1120

AN:

41526

American (AMR)

AF:

0.00608

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68008

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

115

173

230

288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00445

Hom.:

Bravo

AF:

0.00908

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

GLI2-related disorder (1)

Holoprosencephaly 9 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

-1.4

PromoterAI

0.018

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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