Genetic Variant GLI2:c.1317+25C>T (chr2-120975134-C-T) – 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.1317+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 1,611,900 control chromosomes in the GnomAD database, including 661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 94 hom., cov: 34)

Exomes 𝑓: 0.026 ( 567 hom. )

Consequence

GLI2
NM_001374353.1 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.75

Publications

4 publications found

Variant links:

COSMIC-nc: COSV58044398

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

GLI2 links:

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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=-0.93).

BP6

Variant 2-120975134-C-T is Benign according to our data. Variant chr2-120975134-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 259711.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 = 0.0293 (4461/152334) while in subpopulation AFR AF = 0.0445 (1849/41580). AF 95% confidence interval is 0.0428. There are 94 homozygotes in GnomAd4. There are 2087 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 94 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	UniProt
GLI2	NM_001374353.1	MANE Select	c.1317+25C>T	intron	N/A	NP_001361282.1	A0A7I2PJA1
GLI2	NM_001371271.1		c.1368+25C>T	intron	N/A	NP_001358200.1	P10070-5
GLI2	NM_005270.5		c.1368+25C>T	intron	N/A	NP_005261.2	P10070-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GLI2	ENST00000361492.9	TSL:1 MANE Select	c.1317+25C>T	intron	N/A	ENSP00000354586.5	A0A7I2PJA1
GLI2	ENST00000452319.6	TSL:5	c.1368+25C>T	intron	N/A	ENSP00000390436.1	P10070-5
GLI2	ENST00000934404.1		c.1311+25C>T	intron	N/A	ENSP00000604463.1

Frequencies

GnomAD3 genomes

AF:

0.0293

AC:

4456

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0446

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0232

Gnomad ASJ

AF:

0.0758

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0219

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0258

Gnomad OTH

AF:

0.0310

GnomAD2 exomes

AF:

0.0238

AC:

5931

AN:

249058

AF XY:

0.0238

show subpopulations

Gnomad AFR exome

AF:

0.0454

Gnomad AMR exome

AF:

0.0151

Gnomad ASJ exome

AF:

0.0703

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.00455

Gnomad NFE exome

AF:

0.0271

Gnomad OTH exome

AF:

0.0243

GnomAD4 exome

AF:

0.0260

AC:

37890

AN:

1459566

Hom.:

567

Cov.:

AF XY:

0.0260

AC XY:

18846

AN XY:

726102

show subpopulations

African (AFR)

AF:

0.0436

AC:

1459

AN:

33446

American (AMR)

AF:

0.0166

AC:

740

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0681

AC:

1778

AN:

26108

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39686

South Asian (SAS)

AF:

0.0234

AC:

2019

AN:

86192

European-Finnish (FIN)

AF:

0.00558

AC:

293

AN:

52526

Middle Eastern (MID)

AF:

0.0339

AC:

195

AN:

5748

European-Non Finnish (NFE)

AF:

0.0267

AC:

29617

AN:

1110842

Other (OTH)

AF:

0.0296

AC:

1786

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1747

3494

5240

6987

8734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1152

2304

3456

4608

5760

<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:

0.0293

AC:

4461

AN:

152334

Hom.:

Cov.:

AF XY:

0.0280

AC XY:

2087

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0445

AC:

1849

AN:

41580

American (AMR)

AF:

0.0232

AC:

355

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0758

AC:

263

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.0222

AC:

107

AN:

4828

European-Finnish (FIN)

AF:

0.00349

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0259

AC:

1761

AN:

68036

Other (OTH)

AF:

0.0307

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

234

468

701

935

1169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0306

Hom.:

Bravo

AF:

0.0306

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.071

(source)

DANN

Benign

0.64

PhyloP100

-1.7

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