rs149140724

Variant names:

• chr2-120989968-A-G
• rs149140724
• NM_001374353.1:c.4003A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374353.1(GLI2):​c.4003A>G​(p.Met1335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,611,040 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (17 hom., cov: 33)
  • Exomes 𝑓: 0.013 (135 hom.)
• Consequence: GLI2 NM_001374353.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0870
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018228292).
• BP6: Variant 2-120989968-A-G is Benign according to our data. Variant chr2-120989968-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00939 (1430/152268) while in subpopulation NFE AF = 0.0146 (990/67984). AF 95% confidence interval is 0.0138. There are 17 homozygotes in GnomAd4. There are 683 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.4003A>G	p.Met1335Val	missense	Exon 14 of 14	NP_001361282.1	A0A7I2PJA1
	GLI2	NM_001371271.1		c.4054A>G	p.Met1352Val	missense	Exon 14 of 14	NP_001358200.1	P10070-5
	GLI2	NM_005270.5		c.4054A>G	p.Met1352Val	missense	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.4003A>G	p.Met1335Val	missense	Exon 14 of 14	ENSP00000354586.5	A0A7I2PJA1
	GLI2	ENST00000452319.6	TSL:5	c.4054A>G	p.Met1352Val	missense	Exon 13 of 13	ENSP00000390436.1	P10070-5
	GLI2	ENST00000934404.1		c.3997A>G	p.Met1333Val	missense	Exon 14 of 14	ENSP00000604463.1

Frequencies

GnomAD3 genomes AF: 0.00941 AC: 1431 AN: 152152 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00864 AC: 2080 AN: 240838 AF XY: 0.00887

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.00989

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00256

Gnomad NFE exome AF: 0.0147

Gnomad OTH exome AF: 0.00930

GnomAD4 exome AF: 0.0125 AC: 18252 AN: 1458772 Hom.: 135 Cov.: 34 AF XY: 0.0124 AC XY: 8960 AN XY: 725496

African (AFR) AF: 0.00233 AC: 78 AN: 33450

American (AMR) AF: 0.00370 AC: 165 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 269 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00533 AC: 458 AN: 85922

European-Finnish (FIN) AF: 0.00365 AC: 190 AN: 52058

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5760

European-Non Finnish (NFE) AF: 0.0148 AC: 16439 AN: 1111038

Other (OTH) AF: 0.0104 AC: 624 AN: 60282

GnomAD4 genome AF: 0.00939 AC: 1430 AN: 152268 Hom.: 17 Cov.: 33 AF XY: 0.00917 AC XY: 683 AN XY: 74462

African (AFR) AF: 0.00265 AC: 110 AN: 41576

American (AMR) AF: 0.00666 AC: 102 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00581 AC: 28 AN: 4822

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0146 AC: 990 AN: 67984

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.0117 Hom.: 16

Bravo AF: 0.00916

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00434 AC: 19

ESP6500EA AF: 0.0139 AC: 119

ExAC AF: 0.00918 AC: 1112

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0130

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	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
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.1
DANN	Benign	0.65
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.77	N
PhyloP100		-0.087
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.057
Sift	Benign	0.13	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.089
MVP		0.23
MPC		0.33
ClinPred		0.00088	T
GERP RS		-5.3
Varity_R		0.091
gMVP		0.16
Mutation Taster		=99/1	polymorphism

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: rs149140724; hg19: chr2-121747544; COSMIC: COSV106100072; COSMIC: COSV106100072;