rs149091975

Variant names:

• chr2-120986480-G-A
• rs149091975
• NM_001374353.1:c.2108G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-120986480-G-A
• chr2-120986480-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_001374353.1(GLI2):​c.2108G>A​(p.Arg703His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000285 in 1,614,062 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R703C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: GLI2 NM_001374353.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 7.69
• 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 2-120986480-G-A is Benign according to our data. Variant chr2-120986480-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259723.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000512 (78/152314) while in subpopulation AFR AF = 0.00113 (47/41574). AF 95% confidence interval is 0.000873. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.2108G>A	p.Arg703His	missense	Exon 13 of 14	NP_001361282.1	A0A7I2PJA1
	GLI2	NM_001371271.1		c.2159G>A	p.Arg720His	missense	Exon 13 of 14	NP_001358200.1	P10070-5
	GLI2	NM_005270.5		c.2159G>A	p.Arg720His	missense	Exon 13 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.2108G>A	p.Arg703His	missense	Exon 13 of 14	ENSP00000354586.5	A0A7I2PJA1
	GLI2	ENST00000452319.6	TSL:5	c.2159G>A	p.Arg720His	missense	Exon 12 of 13	ENSP00000390436.1	P10070-5
	GLI2	ENST00000934404.1		c.2102G>A	p.Arg701His	missense	Exon 13 of 14	ENSP00000604463.1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000430 AC: 108 AN: 250946 AF XY: 0.000413

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000432

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000261 AC: 382 AN: 1461748 Hom.: 1 Cov.: 33 AF XY: 0.000274 AC XY: 199 AN XY: 727178

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.000962 AC: 43 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53308

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5762

European-Non Finnish (NFE) AF: 0.000210 AC: 233 AN: 1112000

Other (OTH) AF: 0.000646 AC: 39 AN: 60394

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74468

African (AFR) AF: 0.00113 AC: 47 AN: 41574

American (AMR) AF: 0.000653 AC: 10 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.000744

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Holoprosencephaly 1 (1)
-	1	-	Holoprosencephaly 9 (1)
-	-	1	Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.72
MPC		1.2
ClinPred		0.054	T
GERP RS		5.0
Varity_R		0.38
gMVP		0.36
Mutation Taster		=9/91	disease causing

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: rs149091975; hg19: chr2-121744056; COSMIC: COSV58036894; COSMIC: COSV58036894;