rs10167980

Variant names:

• chr2-120989853-A-G
• rs10167980
• NM_001374353.1:c.3888A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-120989853-A-G
• chr2-120989853-A-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001374353.1(GLI2):​c.3888A>G​(p.Pro1296Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 1,611,978 control chromosomes in the GnomAD database, including 391,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (30061 hom., cov: 35)
  • Exomes 𝑓: 0.70 (360964 hom.)
• Consequence: GLI2 NM_001374353.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.00400
• Publications: 20 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-120989853-A-G is Benign according to our data. Variant chr2-120989853-A-G is described in ClinVar as Benign. ClinVar VariationId is 95273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.004 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.729 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI2	NM_001374353.1	MANE Select	c.3888A>G	p.Pro1296Pro	synonymous	Exon 14 of 14	NP_001361282.1	A0A7I2PJA1
	GLI2	NM_001371271.1		c.3939A>G	p.Pro1313Pro	synonymous	Exon 14 of 14	NP_001358200.1	P10070-5
	GLI2	NM_005270.5		c.3939A>G	p.Pro1313Pro	synonymous	Exon 14 of 14	NP_005261.2	P10070-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI2	ENST00000361492.9	TSL:1 MANE Select	c.3888A>G	p.Pro1296Pro	synonymous	Exon 14 of 14	ENSP00000354586.5	A0A7I2PJA1
	GLI2	ENST00000452319.6	TSL:5	c.3939A>G	p.Pro1313Pro	synonymous	Exon 13 of 13	ENSP00000390436.1	P10070-5
	GLI2	ENST00000934404.1		c.3882A>G	p.Pro1294Pro	synonymous	Exon 14 of 14	ENSP00000604463.1

Frequencies

GnomAD3 genomes AF: 0.612 AC: 93110 AN: 152034 Hom.: 30053 Cov.: 35

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.801

Gnomad AMR AF: 0.630

Gnomad ASJ AF: 0.674

Gnomad EAS AF: 0.488

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.639

GnomAD2 exomes AF: 0.636 AC: 157209 AN: 247246 AF XY: 0.640

Gnomad AFR exome AF: 0.395

Gnomad AMR exome AF: 0.573

Gnomad ASJ exome AF: 0.669

Gnomad EAS exome AF: 0.474

Gnomad FIN exome AF: 0.683

Gnomad NFE exome AF: 0.732

Gnomad OTH exome AF: 0.668

GnomAD4 exome AF: 0.698 AC: 1018503 AN: 1459828 Hom.: 360964 Cov.: 54 AF XY: 0.694 AC XY: 503895 AN XY: 726154

African (AFR) AF: 0.394 AC: 13191 AN: 33462

American (AMR) AF: 0.577 AC: 25733 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 17597 AN: 26116

East Asian (EAS) AF: 0.495 AC: 19636 AN: 39676

South Asian (SAS) AF: 0.526 AC: 45319 AN: 86190

European-Finnish (FIN) AF: 0.679 AC: 35572 AN: 52356

Middle Eastern (MID) AF: 0.634 AC: 3655 AN: 5768

European-Non Finnish (NFE) AF: 0.736 AC: 817539 AN: 1111336

Other (OTH) AF: 0.667 AC: 40261 AN: 60334

GnomAD4 genome AF: 0.612 AC: 93126 AN: 152150 Hom.: 30061 Cov.: 35 AF XY: 0.608 AC XY: 45217 AN XY: 74384

African (AFR) AF: 0.407 AC: 16878 AN: 41512

American (AMR) AF: 0.629 AC: 9624 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 2340 AN: 3470

East Asian (EAS) AF: 0.488 AC: 2519 AN: 5164

South Asian (SAS) AF: 0.506 AC: 2444 AN: 4826

European-Finnish (FIN) AF: 0.670 AC: 7103 AN: 10598

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.735 AC: 49931 AN: 67962

Other (OTH) AF: 0.641 AC: 1353 AN: 2110

Alfa AF: 0.677 Hom.: 15307

Bravo AF: 0.598

Asia WGS AF: 0.492 AC: 1712 AN: 3478

EpiCase AF: 0.739

EpiControl AF: 0.740

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Holoprosencephaly 9 (2)
-	-	1	Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (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	-0.80
CADD	Benign	0.98
DANN	Benign	0.60
PhyloP100		-0.0040
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: rs10167980; hg19: chr2-121747429; COSMIC: COSV58042360; COSMIC: COSV58042360;