2-120971914-C-T

Variant names:

• chr2-120971914-C-T
• rs2592591
• NM_001374353.1:c.1060-27C>T

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.1060-27C>T 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 1,612,492 control chromosomes in the GnomAD database, including 760,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61846 hom., cov: 33)
  • Exomes 𝑓: 0.98 (699039 hom.)
• Consequence: GLI2 NM_001374353.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00100
• Publications: 10 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=-0.82).
• BP6: Variant 2-120971914-C-T is Benign according to our data. Variant chr2-120971914-C-T is described in ClinVar as Benign. ClinVar VariationId is 259709.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.1060-27C>T		intron	N/A	NP_001361282.1
	GLI2	NM_001371271.1		c.1060-27C>T		intron	N/A	NP_001358200.1
	GLI2	NM_005270.5		c.1060-27C>T		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.1060-27C>T		intron	N/A	ENSP00000354586.5
	GLI2	ENST00000433812.1	TSL:1	n.*759-27C>T		intron	N/A	ENSP00000402383.1
	GLI2	ENST00000452319.6	TSL:5	c.1060-27C>T		intron	N/A	ENSP00000390436.1

Frequencies

GnomAD3 genomes AF: 0.890 AC: 135343 AN: 152134 Hom.: 61828 Cov.: 33

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.942

Gnomad ASJ AF: 0.966

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.981

Gnomad FIN AF: 0.996

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.986

Gnomad OTH AF: 0.917

GnomAD2 exomes AF: 0.962 AC: 241589 AN: 251224 AF XY: 0.968

Gnomad AFR exome AF: 0.638

Gnomad AMR exome AF: 0.972

Gnomad ASJ exome AF: 0.968

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.995

Gnomad NFE exome AF: 0.987

Gnomad OTH exome AF: 0.968

GnomAD4 exome AF: 0.977 AC: 1426526 AN: 1460240 Hom.: 699039 Cov.: 35 AF XY: 0.978 AC XY: 710527 AN XY: 726546

African (AFR) AF: 0.631 AC: 21094 AN: 33410

American (AMR) AF: 0.969 AC: 43328 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.968 AC: 25301 AN: 26124

East Asian (EAS) AF: 1.00 AC: 39692 AN: 39696

South Asian (SAS) AF: 0.979 AC: 84398 AN: 86226

European-Finnish (FIN) AF: 0.995 AC: 52704 AN: 52978

Middle Eastern (MID) AF: 0.953 AC: 5499 AN: 5768

European-Non Finnish (NFE) AF: 0.987 AC: 1096494 AN: 1110984

Other (OTH) AF: 0.962 AC: 58016 AN: 60338

GnomAD4 genome AF: 0.889 AC: 135409 AN: 152252 Hom.: 61846 Cov.: 33 AF XY: 0.892 AC XY: 66457 AN XY: 74466

African (AFR) AF: 0.649 AC: 26950 AN: 41502

American (AMR) AF: 0.942 AC: 14408 AN: 15294

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

East Asian (EAS) AF: 0.999 AC: 5177 AN: 5180

South Asian (SAS) AF: 0.982 AC: 4737 AN: 4826

European-Finnish (FIN) AF: 0.996 AC: 10585 AN: 10632

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

European-Non Finnish (NFE) AF: 0.986 AC: 67073 AN: 68026

Other (OTH) AF: 0.918 AC: 1941 AN: 2114

Alfa AF: 0.952 Hom.: 17716

Bravo AF: 0.873

Asia WGS AF: 0.969 AC: 3370 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Holoprosencephaly 9 (1)
-	-	1	not specified (1)
-	-	1	Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.9
DANN	Benign	0.84
PhyloP100		0.0010
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: rs2592591; hg19: chr2-121729490;