rs142793481

Variant names:

• chr2-120968790-C-T
• rs142793481
• NM_001374353.1:c.720C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001374353.1(GLI2):​c.720C>T​(p.Asp240Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,613,764 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0064 (53 hom.)
• Consequence: GLI2 NM_001374353.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.885
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040371716).
• BP6: Variant 2-120968790-C-T is Benign according to our data. Variant chr2-120968790-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.885 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00497 (757/152372) while in subpopulation SAS AF = 0.00745 (36/4830). AF 95% confidence interval is 0.00553. There are 1 homozygotes in GnomAd4. There are 462 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 53 AD,AR gene

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.720C>T	p.Asp240Asp	synonymous	Exon 6 of 14	NP_001361282.1
	GLI2	NM_001371271.1		c.720C>T	p.Asp240Asp	synonymous	Exon 6 of 14	NP_001358200.1
	GLI2	NM_005270.5		c.720C>T	p.Asp240Asp	synonymous	Exon 6 of 14	NP_005261.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLI2	ENST00000361492.9	TSL:1 MANE Select	c.720C>T	p.Asp240Asp	synonymous	Exon 6 of 14	ENSP00000354586.5
	GLI2	ENST00000360874.10	TSL:1	n.307C>T		non_coding_transcript_exon	Exon 3 of 4
	GLI2	ENST00000433812.1	TSL:1	n.*419C>T		non_coding_transcript_exon	Exon 4 of 7	ENSP00000402383.1

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 757 AN: 152254 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00498

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00729 AC: 1833 AN: 251292 AF XY: 0.00737

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00245

Gnomad FIN exome AF: 0.0214

Gnomad NFE exome AF: 0.00575

Gnomad OTH exome AF: 0.00865

GnomAD4 exome AF: 0.00643 AC: 9391 AN: 1461392 Hom.: 53 Cov.: 34 AF XY: 0.00643 AC XY: 4674 AN XY: 727046

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.00957 AC: 428 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26134

East Asian (EAS) AF: 0.00224 AC: 89 AN: 39700

South Asian (SAS) AF: 0.00843 AC: 727 AN: 86250

European-Finnish (FIN) AF: 0.0210 AC: 1113 AN: 53100

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5768

European-Non Finnish (NFE) AF: 0.00589 AC: 6549 AN: 1111850

Other (OTH) AF: 0.00634 AC: 383 AN: 60386

GnomAD4 genome AF: 0.00497 AC: 757 AN: 152372 Hom.: 1 Cov.: 33 AF XY: 0.00620 AC XY: 462 AN XY: 74498

African (AFR) AF: 0.00125 AC: 52 AN: 41594

American (AMR) AF: 0.00359 AC: 55 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5176

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4830

European-Finnish (FIN) AF: 0.0233 AC: 248 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00498 AC: 339 AN: 68044

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00509 Hom.: 2

Bravo AF: 0.00368

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00731 AC: 888

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00456

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Holoprosencephaly 9 (1)
-	-	1	Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	3.2
DANN	Uncertain	0.99
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.89
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.049	D
MVP		0.40
ClinPred		0.023	T
GERP RS		-4.8
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs142793481; hg19: chr2-121726366; COSMIC: COSV58047232;