chr2-120955454-G-A

Variant names:

• chr2-120955454-G-A
• rs12614482
• NM_001374353.1:c.643+24G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374353.1(GLI2):​c.643+24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.918 in 1,495,488 control chromosomes in the GnomAD database, including 642,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (52062 hom., cov: 33)
  • Exomes 𝑓: 0.93 (590549 hom.)
• Consequence: GLI2 NM_001374353.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.372
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-120955454-G-A is Benign according to our data. Variant chr2-120955454-G-A is described in ClinVar as Benign. ClinVar VariationId is 259732.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLI2	NM_001374353.1	c.643+24G>A		intron_variant	Intron 5 of 13	ENST00000361492.9	NP_001361282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI2	ENST00000361492.9	c.643+24G>A		intron_variant	Intron 5 of 13	1	NM_001374353.1	ENSP00000354586.5

Frequencies

GnomAD3 genomes AF: 0.788 AC: 119845 AN: 152094 Hom.: 52059 Cov.: 33

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: 0.956

Gnomad FIN AF: 0.979

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.840

GnomAD2 exomes AF: 0.916 AC: 166619 AN: 181970 AF XY: 0.925

Gnomad AFR exome AF: 0.372

Gnomad AMR exome AF: 0.937

Gnomad ASJ exome AF: 0.885

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.974

Gnomad NFE exome AF: 0.948

Gnomad OTH exome AF: 0.922

GnomAD4 exome AF: 0.933 AC: 1253332 AN: 1343276 Hom.: 590549 Cov.: 20 AF XY: 0.935 AC XY: 623114 AN XY: 666244

African (AFR) AF: 0.350 AC: 10631 AN: 30380

American (AMR) AF: 0.930 AC: 33837 AN: 36366

Ashkenazi Jewish (ASJ) AF: 0.890 AC: 20700 AN: 23266

East Asian (EAS) AF: 1.00 AC: 37691 AN: 37700

South Asian (SAS) AF: 0.954 AC: 74580 AN: 78194

European-Finnish (FIN) AF: 0.974 AC: 48182 AN: 49466

Middle Eastern (MID) AF: 0.896 AC: 4852 AN: 5418

European-Non Finnish (NFE) AF: 0.947 AC: 972419 AN: 1026778

Other (OTH) AF: 0.905 AC: 50440 AN: 55708

GnomAD4 genome AF: 0.788 AC: 119872 AN: 152212 Hom.: 52062 Cov.: 33 AF XY: 0.795 AC XY: 59148 AN XY: 74424

African (AFR) AF: 0.380 AC: 15770 AN: 41512

American (AMR) AF: 0.886 AC: 13557 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 3077 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5133 AN: 5140

South Asian (SAS) AF: 0.957 AC: 4622 AN: 4830

European-Finnish (FIN) AF: 0.979 AC: 10399 AN: 10624

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.946 AC: 64375 AN: 68016

Other (OTH) AF: 0.841 AC: 1777 AN: 2112

Alfa AF: 0.713 Hom.: 12477

Bravo AF: 0.762

Asia WGS AF: 0.933 AC: 3243 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Holoprosencephaly 9 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: 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	-0.84
CADD	Benign	5.1
DANN	Benign	0.50
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12614482; hg19: chr2-121713030;