rs2276553

chr2-120986649-A-Gchr2-120986649-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374353.1(GLI2):c.2242+35A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,568,806 control chromosomes in the GnomAD database, including 381,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30521 hom., cov: 32)
  • Exomes 𝑓: 0.70 (351201 hom.)
• Consequence: GLI2 NM_001374353.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.449

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-120986649-A-G is Benign according to our data. Variant chr2-120986649-A-G is described in ClinVar as [Benign]. Clinvar id is 259725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI2	NM_001374353.1	c.2242+35A>G		intron_variant		ENST00000361492.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI2	ENST00000361492.9	c.2242+35A>G		intron_variant		1	NM_001374353.1	P2

Frequencies

GnomAD3 genomes AF: 0.619 AC: 94071 AN: 151962 Hom.: 30512 Cov.: 32

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.674

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.641

GnomAD3 exomes AF: 0.640 AC: 156446 AN: 244614 Hom.: 51381 AF XY: 0.644 AC XY: 85310 AN XY: 132554

Gnomad AFR exome AF: 0.418

Gnomad AMR exome AF: 0.577

Gnomad ASJ exome AF: 0.669

Gnomad EAS exome AF: 0.500

Gnomad SAS exome AF: 0.522

Gnomad FIN exome AF: 0.684

Gnomad NFE exome AF: 0.734

Gnomad OTH exome AF: 0.671

GnomAD4 exome AF: 0.699 AC: 989991 AN: 1416726 Hom.: 351201 Cov.: 23 AF XY: 0.695 AC XY: 491391 AN XY: 707250

Gnomad4 AFR exome AF: 0.419

Gnomad4 AMR exome AF: 0.580

Gnomad4 ASJ exome AF: 0.674

Gnomad4 EAS exome AF: 0.513

Gnomad4 SAS exome AF: 0.523

Gnomad4 FIN exome AF: 0.679

Gnomad4 NFE exome AF: 0.736

Gnomad4 OTH exome AF: 0.671

GnomAD4 genome AF: 0.619 AC: 94094 AN: 152080 Hom.: 30521 Cov.: 32 AF XY: 0.614 AC XY: 45675 AN XY: 74332

Gnomad4 AFR AF: 0.427

Gnomad4 AMR AF: 0.632

Gnomad4 ASJ AF: 0.674

Gnomad4 EAS AF: 0.510

Gnomad4 SAS AF: 0.506

Gnomad4 FIN AF: 0.670

Gnomad4 NFE AF: 0.735

Gnomad4 OTH AF: 0.643

Alfa AF: 0.646 Hom.: 6506

Bravo AF: 0.606

Asia WGS AF: 0.509 AC: 1770 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Holoprosencephaly 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	7.6
Dann	Benign	0.36

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

Other links and lift over

dbSNP: rs2276553; hg19: chr2-121744225; COSMIC: COSV58048699; COSMIC: COSV58048699;