rs3738880

Variant names:

• chr2-120989380-G-T
• rs3738880
• NM_001374353.1:c.3415G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-120989380-G-T
• chr2-120989380-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374353.1(GLI2):​c.3415G>T​(p.Ala1139Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 1,612,702 control chromosomes in the GnomAD database, including 384,436 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1139V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.61 (29634 hom., cov: 35)
  • Exomes 𝑓: 0.69 (354802 hom.)
• Consequence: GLI2 NM_001374353.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.106
• Publications: 43 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=2.11276E-6).
• BP6: Variant 2-120989380-G-T is Benign according to our data. Variant chr2-120989380-G-T is described in ClinVar as Benign. ClinVar VariationId is 95271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.724 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.3415G>T	p.Ala1139Ser	missense	Exon 14 of 14	NP_001361282.1	A0A7I2PJA1
	GLI2	NM_001371271.1		c.3466G>T	p.Ala1156Ser	missense	Exon 14 of 14	NP_001358200.1	P10070-5
	GLI2	NM_005270.5		c.3466G>T	p.Ala1156Ser	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.3415G>T	p.Ala1139Ser	missense	Exon 14 of 14	ENSP00000354586.5	A0A7I2PJA1
	GLI2	ENST00000452319.6	TSL:5	c.3466G>T	p.Ala1156Ser	missense	Exon 13 of 13	ENSP00000390436.1	P10070-5
	GLI2	ENST00000934404.1		c.3409G>T	p.Ala1137Ser	missense	Exon 14 of 14	ENSP00000604463.1

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92417 AN: 152030 Hom.: 29626 Cov.: 35

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.674

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.729

Gnomad OTH AF: 0.634

GnomAD2 exomes AF: 0.632 AC: 156066 AN: 247018 AF XY: 0.636

Gnomad AFR exome AF: 0.394

Gnomad AMR exome AF: 0.572

Gnomad ASJ exome AF: 0.667

Gnomad EAS exome AF: 0.464

Gnomad FIN exome AF: 0.677

Gnomad NFE exome AF: 0.728

Gnomad OTH exome AF: 0.666

GnomAD4 exome AF: 0.691 AC: 1009779 AN: 1460554 Hom.: 354802 Cov.: 66 AF XY: 0.688 AC XY: 499644 AN XY: 726614

African (AFR) AF: 0.392 AC: 13110 AN: 33472

American (AMR) AF: 0.575 AC: 25727 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 17532 AN: 26130

East Asian (EAS) AF: 0.474 AC: 18819 AN: 39690

South Asian (SAS) AF: 0.521 AC: 44906 AN: 86250

European-Finnish (FIN) AF: 0.674 AC: 35188 AN: 52228

Middle Eastern (MID) AF: 0.628 AC: 3621 AN: 5768

European-Non Finnish (NFE) AF: 0.729 AC: 810945 AN: 1111930

Other (OTH) AF: 0.661 AC: 39931 AN: 60382

GnomAD4 genome AF: 0.608 AC: 92433 AN: 152148 Hom.: 29634 Cov.: 35 AF XY: 0.603 AC XY: 44882 AN XY: 74384

African (AFR) AF: 0.404 AC: 16769 AN: 41512

American (AMR) AF: 0.627 AC: 9590 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 2336 AN: 3468

East Asian (EAS) AF: 0.476 AC: 2455 AN: 5154

South Asian (SAS) AF: 0.501 AC: 2421 AN: 4834

European-Finnish (FIN) AF: 0.661 AC: 7010 AN: 10604

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.730 AC: 49573 AN: 67954

Other (OTH) AF: 0.636 AC: 1344 AN: 2112

Alfa AF: 0.679 Hom.: 104123

Bravo AF: 0.594

TwinsUK AF: 0.718 AC: 2661

ALSPAC AF: 0.723 AC: 2787

ESP6500AA AF: 0.413 AC: 1801

ESP6500EA AF: 0.731 AC: 6231

ExAC AF: 0.627 AC: 75614

Asia WGS AF: 0.482 AC: 1677 AN: 3478

EpiCase AF: 0.734

EpiControl AF: 0.736

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Holoprosencephaly 9 (2)
-	-	2	not provided (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
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.15
DANN	Benign	0.79
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0000021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.11
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.019
Sift	Benign	0.52	T
Sift4G	Benign	0.60	T
Polyphen		0.16	B
Vest4		0.010
MPC		0.34
ClinPred		0.0042	T
GERP RS		0.039
Varity_R		0.051
gMVP		0.017
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: rs3738880; hg19: chr2-121746956; COSMIC: COSV58037494; COSMIC: COSV58037494;