NM_001374353.1:c.2437T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001374353.1(GLI2):c.2437T>C(p.Phe813Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,571,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00095 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

GLI2
NM_001374353.1 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.38

Publications

1 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025537461).

BP6

Variant 2-120988402-T-C is Benign according to our data. Variant chr2-120988402-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 235325.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 = 0.000953 (145/152188) while in subpopulation AFR AF = 0.0026 (108/41558). AF 95% confidence interval is 0.0022. There are 0 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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	HGVSp	Effect	Exon Rank	Protein
GLI2	NM_001374353.1	MANE Select	c.2437T>C	p.Phe813Leu	missense	Exon 14 of 14	NP_001361282.1
GLI2	NM_001371271.1		c.2488T>C	p.Phe830Leu	missense	Exon 14 of 14	NP_001358200.1
GLI2	NM_005270.5		c.2488T>C	p.Phe830Leu	missense	Exon 14 of 14	NP_005261.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLI2	ENST00000361492.9	TSL:1 MANE Select	c.2437T>C	p.Phe813Leu	missense	Exon 14 of 14	ENSP00000354586.5
GLI2	ENST00000452319.6	TSL:5	c.2488T>C	p.Phe830Leu	missense	Exon 13 of 13	ENSP00000390436.1
GLI2	ENST00000341310.10	TSL:2	n.*1536T>C		non_coding_transcript_exon	Exon 10 of 10	ENSP00000344473.6

Frequencies

GnomAD3 genomes

AF:

0.000960

AC:

146

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

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:

0.00

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.000135

AC:

AN:

185502

AF XY:

0.0000862

show subpopulations

Gnomad AFR exome

AF:

0.00230

Gnomad AMR exome

AF:

0.000132

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000796

AC:

113

AN:

1419284

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

705216

show subpopulations

African (AFR)

AF:

0.00263

AC:

AN:

30766

American (AMR)

AF:

0.000237

AC:

AN:

42126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24988

East Asian (EAS)

AF:

0.00

AC:

AN:

37300

South Asian (SAS)

AF:

0.00

AC:

AN:

82114

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36228

Middle Eastern (MID)

AF:

0.000352

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101060

Other (OTH)

AF:

0.000322

AC:

AN:

59022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000953

AC:

145

AN:

152188

Hom.:

Cov.:

AF XY:

0.000914

AC XY:

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00260

AC:

108

AN:

41558

American (AMR)

AF:

0.00209

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67954

Other (OTH)

AF:

0.00237

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.00126

ExAC

AF:

0.000146

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (2)

GLI2-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

Eigen

Benign

-0.0033

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.026

MetaSVM

Uncertain

0.10

MutationAssessor

Benign

1.6

PhyloP100

7.4

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.31

Sift

Benign

0.18

Sift4G

Benign

0.46

Polyphen

0.034

Vest4

0.21

MutPred

0.23

Gain of MoRF binding (P = 0.1008)

MVP

0.74

MPC

0.57

ClinPred

0.095

GERP RS

4.6

Varity_R

0.46

gMVP

0.28

Mutation Taster

=87/13

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

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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over