rs78949549

chr2-120984454-C-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.1633-17C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,613,898 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (69 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (74 hom.)
• Consequence: GLI2 NM_001374353.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.974

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=-0.63).
• BP6: Variant 2-120984454-C-T is Benign according to our data. Variant chr2-120984454-C-T is described in ClinVar as [Benign]. Clinvar id is 259718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI2	NM_001374353.1	c.1633-17C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000361492.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI2	ENST00000361492.9	c.1633-17C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001374353.1	P2

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2517 AN: 152176 Hom.: 67 Cov.: 33

Gnomad AFR AF: 0.0555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00464 AC: 1161 AN: 250482 Hom.: 41 AF XY: 0.00340 AC XY: 460 AN XY: 135402

Gnomad AFR exome AF: 0.0589

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000452

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00186 AC: 2720 AN: 1461604 Hom.: 74 Cov.: 32 AF XY: 0.00161 AC XY: 1169 AN XY: 727122

Gnomad4 AFR exome AF: 0.0565

Gnomad4 AMR exome AF: 0.00409

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000244

Gnomad4 OTH exome AF: 0.00515

GnomAD4 genome AF: 0.0166 AC: 2530 AN: 152294 Hom.: 69 Cov.: 33 AF XY: 0.0162 AC XY: 1209 AN XY: 74480

Gnomad4 AFR AF: 0.0557

Gnomad4 AMR AF: 0.00921

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0149 Hom.: 11

Bravo AF: 0.0187

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	7.8
Dann	Benign	0.77

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: rs78949549; hg19: chr2-121742030;