NM_001374353.1:c.643+35T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001374353.1(GLI2):c.643+35T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.916 in 1,364,864 control chromosomes in the GnomAD database, including 584,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.79 ( 52061 hom., cov: 33)

Exomes 𝑓: 0.93 ( 532376 hom. )

Consequence

GLI2
NM_001374353.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.895

Publications

8 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: 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:

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=-0.85).

BP6

Variant 2-120955465-T-C is Benign according to our data. Variant chr2-120955465-T-C is described in ClinVar as Benign. ClinVar VariationId is 259733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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	UniProt
GLI2	NM_001374353.1	MANE Select	c.643+35T>C	intron	N/A	NP_001361282.1	A0A7I2PJA1
GLI2	NM_001371271.1		c.643+35T>C	intron	N/A	NP_001358200.1	P10070-5
GLI2	NM_005270.5		c.643+35T>C	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.643+35T>C	intron	N/A	ENSP00000354586.5	A0A7I2PJA1
GLI2	ENST00000360874.10	TSL:1	n.231-13249T>C	intron	N/A
GLI2	ENST00000433812.1	TSL:1	n.*342+35T>C	intron	N/A	ENSP00000402383.1	H7C1U2

Frequencies

GnomAD3 genomes

AF:

0.788

AC:

119839

AN:

152068

Hom.:

52058

Cov.:

show subpopulations

Gnomad AFR

AF:

0.380

Gnomad AMI

AF:

0.995

Gnomad AMR

AF:

0.886

Gnomad ASJ

AF:

0.886

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.957

Gnomad FIN

AF:

0.979

Gnomad MID

AF:

0.867

Gnomad NFE

AF:

0.947

Gnomad OTH

AF:

0.840

GnomAD2 exomes

AF:

0.913

AC:

142153

AN:

155738

AF XY:

0.922

show subpopulations

Gnomad AFR exome

AF:

0.373

Gnomad AMR exome

AF:

0.934

Gnomad ASJ exome

AF:

0.879

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.973

Gnomad NFE exome

AF:

0.946

Gnomad OTH exome

AF:

0.918

GnomAD4 exome

AF:

0.932

AC:

1130477

AN:

1212678

Hom.:

532376

Cov.:

AF XY:

0.934

AC XY:

564548

AN XY:

604172

show subpopulations

African (AFR)

AF:

0.347

AC:

9706

AN:

27964

American (AMR)

AF:

0.927

AC:

29426

AN:

31758

Ashkenazi Jewish (ASJ)

AF:

0.888

AC:

19015

AN:

21422

East Asian (EAS)

AF:

1.00

AC:

36525

AN:

36532

South Asian (SAS)

AF:

0.953

AC:

69160

AN:

72594

European-Finnish (FIN)

AF:

0.974

AC:

46231

AN:

47472

Middle Eastern (MID)

AF:

0.895

AC:

4558

AN:

5094

European-Non Finnish (NFE)

AF:

0.947

AC:

869518

AN:

918582

Other (OTH)

AF:

0.904

AC:

46338

AN:

51260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

3184

6367

9551

12734

15918

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17206

34412

51618

68824

86030

<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:

0.788

AC:

119866

AN:

152186

Hom.:

52061

Cov.:

AF XY:

0.795

AC XY:

59147

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.380

AC:

15760

AN:

41494

American (AMR)

AF:

0.886

AC:

13561

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.886

AC:

3077

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5128

AN:

5134

South Asian (SAS)

AF:

0.957

AC:

4621

AN:

4828

European-Finnish (FIN)

AF:

0.979

AC:

10403

AN:

10628

Middle Eastern (MID)

AF:

0.867

AC:

255

AN:

294

European-Non Finnish (NFE)

AF:

0.947

AC:

64379

AN:

68012

Other (OTH)

AF:

0.841

AC:

1775

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

819

1637

2456

3274

4093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

828

1656

2484

3312

4140

<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:

0.716

Hom.:

13902

Bravo

AF:

0.762

Asia WGS

AF:

0.932

AC:

3242

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Holoprosencephaly 9 (1)

not specified (1)

Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.36

(source)

DANN

Benign

0.42

PhyloP100

-0.90

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