2-120982929-C-T

Variant names:

• chr2-120982929-C-T
• rs280196
• NM_001374353.1:c.1632+49C>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.1632+49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.926 in 1,586,752 control chromosomes in the GnomAD database, including 692,339 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (52888 hom., cov: 33)
  • Exomes 𝑓: 0.94 (639451 hom.)
• Consequence: GLI2 NM_001374353.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.290
• Publications: 7 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=-0.86).
• BP6: Variant 2-120982929-C-T is Benign according to our data. Variant chr2-120982929-C-T is described in ClinVar as Benign. ClinVar VariationId is 259717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 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.1632+49C>T		intron	N/A	NP_001361282.1
	GLI2	NM_001371271.1		c.1683+49C>T		intron	N/A	NP_001358200.1
	GLI2	NM_005270.5		c.1683+49C>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.1632+49C>T		intron	N/A	ENSP00000354586.5
	GLI2	ENST00000452319.6	TSL:5	c.1683+49C>T		intron	N/A	ENSP00000390436.1
	GLI2	ENST00000341310.10	TSL:2	n.*731+49C>T		intron	N/A	ENSP00000344473.6

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121294 AN: 152060 Hom.: 52882 Cov.: 33

Gnomad AFR AF: 0.406

Gnomad AMI AF: 0.993

Gnomad AMR AF: 0.875

Gnomad ASJ AF: 0.874

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.946

Gnomad FIN AF: 0.991

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.954

Gnomad OTH AF: 0.834

GnomAD2 exomes AF: 0.916 AC: 221664 AN: 241978 AF XY: 0.927

Gnomad AFR exome AF: 0.392

Gnomad AMR exome AF: 0.937

Gnomad ASJ exome AF: 0.881

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.990

Gnomad NFE exome AF: 0.953

Gnomad OTH exome AF: 0.926

GnomAD4 exome AF: 0.940 AC: 1348400 AN: 1434574 Hom.: 639451 Cov.: 27 AF XY: 0.942 AC XY: 669606 AN XY: 711156

African (AFR) AF: 0.386 AC: 12687 AN: 32864

American (AMR) AF: 0.930 AC: 40923 AN: 43996

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 22371 AN: 25368

East Asian (EAS) AF: 1.00 AC: 39251 AN: 39268

South Asian (SAS) AF: 0.943 AC: 79505 AN: 84320

European-Finnish (FIN) AF: 0.989 AC: 51776 AN: 52358

Middle Eastern (MID) AF: 0.887 AC: 4953 AN: 5586

European-Non Finnish (NFE) AF: 0.956 AC: 1043070 AN: 1091622

Other (OTH) AF: 0.910 AC: 53864 AN: 59192

GnomAD4 genome AF: 0.797 AC: 121329 AN: 152178 Hom.: 52888 Cov.: 33 AF XY: 0.805 AC XY: 59881 AN XY: 74398

African (AFR) AF: 0.406 AC: 16833 AN: 41470

American (AMR) AF: 0.875 AC: 13383 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.874 AC: 3035 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5159 AN: 5170

South Asian (SAS) AF: 0.946 AC: 4564 AN: 4826

European-Finnish (FIN) AF: 0.991 AC: 10527 AN: 10618

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.954 AC: 64906 AN: 68010

Other (OTH) AF: 0.836 AC: 1766 AN: 2112

Alfa AF: 0.893 Hom.: 32977

Bravo AF: 0.771

Asia WGS AF: 0.926 AC: 3219 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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.9
DANN	Benign	0.48
PhyloP100		0.29
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: rs280196; hg19: chr2-121740505;