NM_001374353.1:c.254+32C>T

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.254+32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,449,786 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00098 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0011 ( 22 hom. )

Consequence

GLI2
NM_001374353.1 intron

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.166

Publications

0 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

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=-0.83).
BP6
Variant 2-120927498-C-T is Benign according to our data. Variant chr2-120927498-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000985 (150/152340) while in subpopulation SAS AF = 0.00973 (47/4830). AF 95% confidence interval is 0.00752. There are 1 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 22 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GLI2NM_001374353.1 linkc.254+32C>T intron_variant Intron 3 of 13 ENST00000361492.9 NP_001361282.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GLI2ENST00000361492.9 linkc.254+32C>T intron_variant Intron 3 of 13 1 NM_001374353.1 ENSP00000354586.5 A0A7I2PJA1

Frequencies

GnomAD3 genomes
AF:
0.000992
AC:
151
AN:
152222
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00373
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00993
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000485
Gnomad OTH
AF:
0.00143
GnomAD2 exomes
AF:
0.00195
AC:
490
AN:
251070
AF XY:
0.00252
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000665
Gnomad ASJ exome
AF:
0.00129
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000519
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.00108
AC:
1398
AN:
1297446
Hom.:
22
Cov.:
20
AF XY:
0.00143
AC XY:
933
AN XY:
654112
show subpopulations
African (AFR)
AF:
0.000166
AC:
5
AN:
30174
American (AMR)
AF:
0.000719
AC:
32
AN:
44522
Ashkenazi Jewish (ASJ)
AF:
0.000996
AC:
25
AN:
25098
East Asian (EAS)
AF:
0.0000514
AC:
2
AN:
38914
South Asian (SAS)
AF:
0.0111
AC:
926
AN:
83102
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53126
Middle Eastern (MID)
AF:
0.00587
AC:
32
AN:
5456
European-Non Finnish (NFE)
AF:
0.000301
AC:
290
AN:
961944
Other (OTH)
AF:
0.00156
AC:
86
AN:
55110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
85
171
256
342
427
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.000985
AC:
150
AN:
152340
Hom.:
1
Cov.:
33
AF XY:
0.00114
AC XY:
85
AN XY:
74484
show subpopulations
African (AFR)
AF:
0.0000962
AC:
4
AN:
41578
American (AMR)
AF:
0.00372
AC:
57
AN:
15310
Ashkenazi Jewish (ASJ)
AF:
0.00173
AC:
6
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.00973
AC:
47
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000485
AC:
33
AN:
68030
Other (OTH)
AF:
0.00142
AC:
3
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.507
Heterozygous variant carriers
0
9
17
26
34
43
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
4
8
12
16
20
<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:
0.000610
Hom.:
0
Bravo
AF:
0.00101
Asia WGS
AF:
0.00318
AC:
11
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Mar 28, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
CADD
Benign
3.1
DANN
Benign
0.68
PhyloP100
-0.17
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs183122114; hg19: chr2-121685074; API