rs149894186

Positions:

• chr2-120970510-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001374353.1(GLI2):​c.963C>G​(p.Pro321=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,614,050 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (48 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (45 hom.)
• Consequence: GLI2 NM_001374353.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.215

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-120970510-C-G is Benign according to our data. Variant chr2-120970510-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 259738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-120970510-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.215 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0134 (2034/152286) while in subpopulation AFR AF= 0.0445 (1850/41548). AF 95% confidence interval is 0.0428. There are 48 homozygotes in gnomad4. There are 955 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2034 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI2	NM_001374353.1	c.963C>G	p.Pro321=	synonymous_variant	7/14	ENST00000361492.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI2	ENST00000361492.9	c.963C>G	p.Pro321=	synonymous_variant	7/14	1	NM_001374353.1	P2

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2025 AN: 152168 Hom.: 48 Cov.: 33

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00394 AC: 991 AN: 251414 Hom.: 20 AF XY: 0.00289 AC XY: 393 AN XY: 135892

Gnomad AFR exome AF: 0.0487

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00156 AC: 2278 AN: 1461764 Hom.: 45 Cov.: 33 AF XY: 0.00135 AC XY: 980 AN XY: 727200

Gnomad4 AFR exome AF: 0.0468

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.00412

GnomAD4 genome AF: 0.0134 AC: 2034 AN: 152286 Hom.: 48 Cov.: 33 AF XY: 0.0128 AC XY: 955 AN XY: 74454

Gnomad4 AFR AF: 0.0445

Gnomad4 AMR AF: 0.00823

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00229 Hom.: 7

Bravo AF: 0.0154

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Holoprosencephaly 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.7
DANN	Benign	0.80

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: rs149894186; hg19: chr2-121728086; COSMIC: COSV58037357; COSMIC: COSV58037357;