rs2592595

Variant names:

• chr2-120968871-G-A
• rs2592595
• NM_001374353.1:c.801G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-120968871-G-A
• chr2-120968871-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001374353.1(GLI2):​c.801G>A​(p.Ser267Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.959 in 1,613,450 control chromosomes in the GnomAD database, including 751,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S267S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.84 (57441 hom., cov: 33)
  • Exomes 𝑓: 0.97 (693937 hom.)
• Consequence: GLI2 NM_001374353.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -5.92
• Publications: 24 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=7.7370595E-7).
• BP6: Variant 2-120968871-G-A is Benign according to our data. Variant chr2-120968871-G-A is described in ClinVar as Benign. ClinVar VariationId is 259736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.979 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.801G>A	p.Ser267Ser	synonymous	Exon 6 of 14	NP_001361282.1
	GLI2	NM_001371271.1		c.801G>A	p.Ser267Ser	synonymous	Exon 6 of 14	NP_001358200.1
	GLI2	NM_005270.5		c.801G>A	p.Ser267Ser	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.801G>A	p.Ser267Ser	synonymous	Exon 6 of 14	ENSP00000354586.5
	GLI2	ENST00000360874.10	TSL:1	n.388G>A		non_coding_transcript_exon	Exon 3 of 4
	GLI2	ENST00000433812.1	TSL:1	n.*500G>A		non_coding_transcript_exon	Exon 4 of 7	ENSP00000402383.1

Frequencies

GnomAD3 genomes AF: 0.840 AC: 127750 AN: 152102 Hom.: 57432 Cov.: 33

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.924

Gnomad ASJ AF: 0.966

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.980

Gnomad FIN AF: 0.996

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.889

GnomAD2 exomes AF: 0.949 AC: 238228 AN: 251088 AF XY: 0.959

Gnomad AFR exome AF: 0.465

Gnomad AMR exome AF: 0.963

Gnomad ASJ exome AF: 0.968

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.995

Gnomad NFE exome AF: 0.986

Gnomad OTH exome AF: 0.962

GnomAD4 exome AF: 0.971 AC: 1418808 AN: 1461228 Hom.: 693937 Cov.: 55 AF XY: 0.973 AC XY: 707184 AN XY: 726942

African (AFR) AF: 0.445 AC: 14898 AN: 33476

American (AMR) AF: 0.959 AC: 42894 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.968 AC: 25298 AN: 26128

East Asian (EAS) AF: 1.00 AC: 39693 AN: 39698

South Asian (SAS) AF: 0.978 AC: 84393 AN: 86254

European-Finnish (FIN) AF: 0.995 AC: 52695 AN: 52974

Middle Eastern (MID) AF: 0.939 AC: 5416 AN: 5768

European-Non Finnish (NFE) AF: 0.986 AC: 1096218 AN: 1111824

Other (OTH) AF: 0.949 AC: 57303 AN: 60386

GnomAD4 genome AF: 0.840 AC: 127800 AN: 152222 Hom.: 57441 Cov.: 33 AF XY: 0.845 AC XY: 62874 AN XY: 74430

African (AFR) AF: 0.476 AC: 19754 AN: 41482

American (AMR) AF: 0.924 AC: 14137 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.966 AC: 3353 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5151 AN: 5156

South Asian (SAS) AF: 0.981 AC: 4728 AN: 4822

European-Finnish (FIN) AF: 0.996 AC: 10579 AN: 10626

Middle Eastern (MID) AF: 0.925 AC: 272 AN: 294

European-Non Finnish (NFE) AF: 0.985 AC: 67035 AN: 68040

Other (OTH) AF: 0.890 AC: 1882 AN: 2114

Alfa AF: 0.876 Hom.: 51528

Bravo AF: 0.816

TwinsUK AF: 0.988 AC: 3665

ALSPAC AF: 0.987 AC: 3802

ESP6500AA AF: 0.468 AC: 2064

ESP6500EA AF: 0.984 AC: 8461

ExAC AF: 0.940 AC: 114060

Asia WGS AF: 0.959 AC: 3334 AN: 3478

EpiCase AF: 0.985

EpiControl AF: 0.985

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.014
DANN	Benign	0.86
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	7.7e-7	T
MetaSVM	Benign	-0.99	T
PhyloP100		-5.9
PROVEAN	Benign	0.91	N
REVEL	Benign	0.026
Sift	Benign	0.99	T
ClinPred		0.016	T
GERP RS		-9.8
Mutation Taster		=95/5	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: rs2592595; hg19: chr2-121726447; COSMIC: COSV108118174;