rs41279790

chr2-120982917-G-Achr2-120982917-G-Cchr2-120982917-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374353.1(GLI2):c.1632+37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,602,258 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (10 hom., cov: 33)
  • Exomes 𝑓: 0.014 (145 hom.)
• Consequence: GLI2 NM_001374353.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.244

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=-0.86).
• BP6: Variant 2-120982917-G-A is Benign according to our data. Variant chr2-120982917-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0104 (1589/152310) while in subpopulation NFE AF= 0.0169 (1146/68012). AF 95% confidence interval is 0.016. There are 10 homozygotes in gnomad4. There are 726 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1589 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI2	NM_001374353.1	c.1632+37G>A		intron_variant		ENST00000361492.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI2	ENST00000361492.9	c.1632+37G>A		intron_variant		1	NM_001374353.1	P2

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1589 AN: 152192 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.0106 AC: 2603 AN: 245888 Hom.: 25 AF XY: 0.0107 AC XY: 1427 AN XY: 133082

Gnomad AFR exome AF: 0.00280

Gnomad AMR exome AF: 0.00918

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00359

Gnomad FIN exome AF: 0.00622

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0141 AC: 20498 AN: 1449948 Hom.: 145 Cov.: 31 AF XY: 0.0137 AC XY: 9892 AN XY: 719660

Gnomad4 AFR exome AF: 0.00237

Gnomad4 AMR exome AF: 0.00962

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00325

Gnomad4 FIN exome AF: 0.00674

Gnomad4 NFE exome AF: 0.0164

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.0104 AC: 1589 AN: 152310 Hom.: 10 Cov.: 33 AF XY: 0.00975 AC XY: 726 AN XY: 74482

Gnomad4 AFR AF: 0.00298

Gnomad4 AMR AF: 0.00981

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.0169

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00600 Hom.: 3

Bravo AF: 0.0108

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.83
Dann	Benign	0.48

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: rs41279790; hg19: chr2-121740493; COSMIC: COSV58035808;