rs2276553

Variant names:

• chr2-120986649-A-G
• rs2276553
• NM_001374353.1:c.2242+35A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-120986649-A-G
• chr2-120986649-A-T

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.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:5
• Conservation: PhyloP100: 0.449
• 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=-0.91).
• BP6: Variant 2-120986649-A-G is Benign according to our data. Variant chr2-120986649-A-G is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
GLI2	NM_001374353.1	c.2242+35A>G		intron_variant	Intron 13 of 13	ENST00000361492.9	NP_001361282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLI2	ENST00000361492.9	c.2242+35A>G		intron_variant	Intron 13 of 13	1	NM_001374353.1	ENSP00000354586.5

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

GnomAD2 exomes AF: 0.640 AC: 156446 AN: 244614 AF XY: 0.644

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 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

African (AFR) AF: 0.419 AC: 13621 AN: 32534

American (AMR) AF: 0.580 AC: 25742 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 17345 AN: 25740

East Asian (EAS) AF: 0.513 AC: 20234 AN: 39420

South Asian (SAS) AF: 0.523 AC: 44425 AN: 84980

European-Finnish (FIN) AF: 0.679 AC: 36012 AN: 53008

Middle Eastern (MID) AF: 0.641 AC: 3466 AN: 5408

European-Non Finnish (NFE) AF: 0.736 AC: 789637 AN: 1072360

Other (OTH) AF: 0.671 AC: 39509 AN: 58864

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

African (AFR) AF: 0.427 AC: 17703 AN: 41480

American (AMR) AF: 0.632 AC: 9660 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 2339 AN: 3470

East Asian (EAS) AF: 0.510 AC: 2638 AN: 5170

South Asian (SAS) AF: 0.506 AC: 2437 AN: 4818

European-Finnish (FIN) AF: 0.670 AC: 7091 AN: 10580

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.735 AC: 49932 AN: 67954

Other (OTH) AF: 0.643 AC: 1358 AN: 2112

Alfa AF: 0.662 Hom.: 11737

Bravo AF: 0.606

Asia WGS AF: 0.509 AC: 1770 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	-0.91
CADD	Benign	7.6
DANN	Benign	0.36
PhyloP100		0.45
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: rs2276553; hg19: chr2-121744225; COSMIC: COSV58048699; COSMIC: COSV58048699;