2-120975035-G-A

Position:

chr2-120975035-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001374353.1(GLI2):c.1243G>A(p.Val415Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000852 in 1,614,106 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 6 hom., cov: 34)

Exomes 𝑓: 0.00053 ( 6 hom. )

Consequence

GLI2
NM_001374353.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 10.0

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008425355).

BP6

Variant 2-120975035-G-A is Benign according to our data. Variant chr2-120975035-G-A is described in ClinVar as [Benign]. Clinvar id is 198817.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 = 0.00392 (597/152388) while in subpopulation AFR AF= 0.0128 (531/41594). AF 95% confidence interval is 0.0119. There are 6 homozygotes in gnomad4. There are 279 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 597 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI2	NM_001374353.1 linkuse as main transcript	c.1243G>A	p.Val415Met	missense_variant	9/14	ENST00000361492.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI2	ENST00000361492.9 linkuse as main transcript	c.1243G>A	p.Val415Met	missense_variant	9/14	1	NM_001374353.1	P2

Frequencies

GnomAD3 genomes

AF:

0.00393

AC:

598

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00124

AC:

313

AN:

251424

Hom.:

AF XY:

0.000846

AC XY:

115

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00516

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000237

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000532

AC:

778

AN:

1461718

Hom.:

Cov.:

AF XY:

0.000481

AC XY:

350

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.0112

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00589

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00392

AC:

597

AN:

152388

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

279

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.0128

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00662

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000900

Hom.:

Bravo

AF:

0.00471

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00151

AC:

183

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 29, 2015

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Holoprosencephaly 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;D

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

.;T

MetaRNN

Benign

0.0084

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

0.56

D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.14

Sift

Benign

0.096

T;T

Sift4G

Uncertain

0.039

D;D

Polyphen

0.99

D;D

Vest4

0.53

MVP

0.39

MPC

0.92

ClinPred

0.042

GERP RS

4.3

Varity_R

0.12

gMVP

0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over