2-120972110-T-C

Variant names:

• chr2-120972110-T-C
• rs2592590
• NM_001374353.1:c.1182+47T>C

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.1182+47T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.969 in 1,609,734 control chromosomes in the GnomAD database, including 759,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61867 hom., cov: 35)
  • Exomes 𝑓: 0.98 (697720 hom.)
• Consequence: GLI2 NM_001374353.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.55
• Publications: 6 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=-0.94).
• BP6: Variant 2-120972110-T-C is Benign according to our data. Variant chr2-120972110-T-C is described in ClinVar as Benign. ClinVar VariationId is 259710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.98 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374353.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI2	NM_001374353.1	MANE Select	c.1182+47T>C		intron	N/A	NP_001361282.1
	GLI2	NM_001371271.1		c.1182+47T>C		intron	N/A	NP_001358200.1
	GLI2	NM_005270.5		c.1182+47T>C		intron	N/A	NP_005261.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI2	ENST00000361492.9	TSL:1 MANE Select	c.1182+47T>C		intron	N/A	ENSP00000354586.5
	GLI2	ENST00000433812.1	TSL:1	n.*881+47T>C		intron	N/A	ENSP00000402383.1
	GLI2	ENST00000452319.6	TSL:5	c.1182+47T>C		intron	N/A	ENSP00000390436.1

Frequencies

GnomAD3 genomes AF: 0.890 AC: 135379 AN: 152156 Hom.: 61849 Cov.: 35

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.942

Gnomad ASJ AF: 0.966

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.981

Gnomad FIN AF: 0.996

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.986

Gnomad OTH AF: 0.918

GnomAD2 exomes AF: 0.962 AC: 237340 AN: 246640 AF XY: 0.968

Gnomad AFR exome AF: 0.638

Gnomad AMR exome AF: 0.972

Gnomad ASJ exome AF: 0.969

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.995

Gnomad NFE exome AF: 0.987

Gnomad OTH exome AF: 0.967

GnomAD4 exome AF: 0.977 AC: 1423825 AN: 1457460 Hom.: 697720 Cov.: 32 AF XY: 0.978 AC XY: 709225 AN XY: 725214

African (AFR) AF: 0.631 AC: 21069 AN: 33376

American (AMR) AF: 0.969 AC: 43276 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.969 AC: 25264 AN: 26084

East Asian (EAS) AF: 1.00 AC: 39656 AN: 39660

South Asian (SAS) AF: 0.979 AC: 83996 AN: 85816

European-Finnish (FIN) AF: 0.995 AC: 52054 AN: 52326

Middle Eastern (MID) AF: 0.954 AC: 4839 AN: 5072

European-Non Finnish (NFE) AF: 0.987 AC: 1095792 AN: 1110272

Other (OTH) AF: 0.962 AC: 57879 AN: 60190

GnomAD4 genome AF: 0.889 AC: 135445 AN: 152274 Hom.: 61867 Cov.: 35 AF XY: 0.893 AC XY: 66448 AN XY: 74450

African (AFR) AF: 0.650 AC: 26974 AN: 41512

American (AMR) AF: 0.942 AC: 14420 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.966 AC: 3353 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5166 AN: 5168

South Asian (SAS) AF: 0.981 AC: 4740 AN: 4830

European-Finnish (FIN) AF: 0.996 AC: 10581 AN: 10628

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.986 AC: 67084 AN: 68038

Other (OTH) AF: 0.919 AC: 1942 AN: 2114

Alfa AF: 0.939 Hom.: 12602

Bravo AF: 0.873

Asia WGS AF: 0.969 AC: 3370 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.2
DANN	Benign	0.62
PhyloP100		-1.6
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: rs2592590; hg19: chr2-121729686;