rs114376238

Variant names:

• chr2-120989857-C-T
• rs114376238
• NM_001374353.1:c.3892C>T

Variant summary

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

The NM_005270.5(GLI2):​c.3943C>T​(p.Pro1315Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,612,970 control chromosomes in the GnomAD database, including 588 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 0.017 (35 hom., cov: 33)
  • Exomes 𝑓: 0.025 (553 hom.)
• Consequence: GLI2 NM_005270.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0310
• Publications: 6 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 (MetaRNN=0.0033062696).
• BP6: Variant 2-120989857-C-T is Benign according to our data. Variant chr2-120989857-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95274.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 = 0.0168 (2562/152358) while in subpopulation NFE AF = 0.0275 (1870/68018). AF 95% confidence interval is 0.0265. There are 35 homozygotes in GnomAd4. There are 1176 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005270.5. 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.3892C>T	p.Pro1298Ser	missense	Exon 14 of 14	NP_001361282.1
	GLI2	NM_001371271.1		c.3943C>T	p.Pro1315Ser	missense	Exon 14 of 14	NP_001358200.1
	GLI2	NM_005270.5		c.3943C>T	p.Pro1315Ser	missense	Exon 14 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.3892C>T	p.Pro1298Ser	missense	Exon 14 of 14	ENSP00000354586.5
	GLI2	ENST00000452319.6	TSL:5	c.3943C>T	p.Pro1315Ser	missense	Exon 13 of 13	ENSP00000390436.1
	GLI2	ENST00000934404.1		c.3886C>T	p.Pro1296Ser	missense	Exon 14 of 14	ENSP00000604463.1

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2563 AN: 152240 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.00453

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0275

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0163 AC: 4054 AN: 248274 AF XY: 0.0168

Gnomad AFR exome AF: 0.00386

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.00812

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00715

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0159

GnomAD4 exome AF: 0.0249 AC: 36430 AN: 1460612 Hom.: 553 Cov.: 34 AF XY: 0.0246 AC XY: 17889 AN XY: 726606

African (AFR) AF: 0.00281 AC: 94 AN: 33478

American (AMR) AF: 0.0107 AC: 479 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00896 AC: 234 AN: 26124

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39694

South Asian (SAS) AF: 0.0159 AC: 1372 AN: 86240

European-Finnish (FIN) AF: 0.00811 AC: 425 AN: 52412

Middle Eastern (MID) AF: 0.0142 AC: 82 AN: 5766

European-Non Finnish (NFE) AF: 0.0291 AC: 32387 AN: 1111828

Other (OTH) AF: 0.0224 AC: 1351 AN: 60370

GnomAD4 genome AF: 0.0168 AC: 2562 AN: 152358 Hom.: 35 Cov.: 33 AF XY: 0.0158 AC XY: 1176 AN XY: 74508

African (AFR) AF: 0.00452 AC: 188 AN: 41594

American (AMR) AF: 0.0165 AC: 253 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4824

European-Finnish (FIN) AF: 0.00725 AC: 77 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0275 AC: 1870 AN: 68018

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0230 Hom.: 109

Bravo AF: 0.0161

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0246 AC: 95

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.0267 AC: 230

ExAC AF: 0.0162 AC: 1971

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0262

EpiControl AF: 0.0251

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	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	0.061
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.0
DANN	Benign	0.24
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.031
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.017
Sift	Benign	0.65	T
Sift4G	Benign	0.42	T
Polyphen		0.0010	B
Vest4		0.029
MPC		0.33
ClinPred		0.0016	T
GERP RS		1.0
Varity_R		0.067
gMVP		0.13
Mutation Taster		=98/2	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: rs114376238; hg19: chr2-121747433; COSMIC: COSV58044406;