rs2592595

chr2-120968871-G-Achr2-120968871-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001374353.1(GLI2):c.801G>A(p.Ser267=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.959 in 1,613,450 control chromosomes in the GnomAD database, including 751,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (57441 hom., cov: 33)
  • Exomes 𝑓: 0.97 (693937 hom.)
• Consequence: GLI2 NM_001374353.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.92

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 (MetaRNN=7.7370595E-7).
• BP6: Variant 2-120968871-G-A is Benign according to our data. Variant chr2-120968871-G-A is described in ClinVar as [Benign]. Clinvar id is 259736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-120968871-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLI2	NM_001374353.1	c.801G>A	p.Ser267=	synonymous_variant	6/14	ENST00000361492.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLI2	ENST00000361492.9	c.801G>A	p.Ser267=	synonymous_variant	6/14	1	NM_001374353.1	P2

Frequencies

GnomAD3 genomes AF: 0.840 AC: 127750 AN: 152102 Hom.: 57432 Cov.: 33

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.924

Gnomad ASJ AF: 0.966

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.980

Gnomad FIN AF: 0.996

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.889

GnomAD3 exomes AF: 0.949 AC: 238228 AN: 251088 Hom.: 115106 AF XY: 0.959 AC XY: 130207 AN XY: 135818

Gnomad AFR exome AF: 0.465

Gnomad AMR exome AF: 0.963

Gnomad ASJ exome AF: 0.968

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.979

Gnomad FIN exome AF: 0.995

Gnomad NFE exome AF: 0.986

Gnomad OTH exome AF: 0.962

GnomAD4 exome AF: 0.971 AC: 1418808 AN: 1461228 Hom.: 693937 Cov.: 55 AF XY: 0.973 AC XY: 707184 AN XY: 726942

Gnomad4 AFR exome AF: 0.445

Gnomad4 AMR exome AF: 0.959

Gnomad4 ASJ exome AF: 0.968

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.978

Gnomad4 FIN exome AF: 0.995

Gnomad4 NFE exome AF: 0.986

Gnomad4 OTH exome AF: 0.949

GnomAD4 genome AF: 0.840 AC: 127800 AN: 152222 Hom.: 57441 Cov.: 33 AF XY: 0.845 AC XY: 62874 AN XY: 74430

Gnomad4 AFR AF: 0.476

Gnomad4 AMR AF: 0.924

Gnomad4 ASJ AF: 0.966

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.981

Gnomad4 FIN AF: 0.996

Gnomad4 NFE AF: 0.985

Gnomad4 OTH AF: 0.890

Alfa AF: 0.921 Hom.: 38313

Bravo AF: 0.816

TwinsUK AF: 0.988 AC: 3665

ALSPAC AF: 0.987 AC: 3802

ESP6500AA AF: 0.468 AC: 2064

ESP6500EA AF: 0.984 AC: 8461

ExAC AF: 0.940 AC: 114060

Asia WGS AF: 0.959 AC: 3334 AN: 3478

EpiCase AF: 0.985

EpiControl AF: 0.985

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Holoprosencephaly 9 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 28, 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_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	0.014
Dann	Benign	0.86
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	7.7e-7	T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	2.5e-14	P;P;P
PROVEAN	Benign	0.91	N
REVEL	Benign	0.026
Sift	Benign	0.99	T
ClinPred		0.016	T
GERP RS		-9.8

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: rs2592595; hg19: chr2-121726447;