rs146811565

Variant names:

• chr2-120988854-C-T
• rs146811565
• NM_001374353.1:c.2889C>T

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.2889C>T​(p.Ser963Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00812 in 1,490,924 control chromosomes in the GnomAD database, including 853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (510 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (343 hom.)
• Consequence: GLI2 NM_001374353.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.78
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-120988854-C-T is Benign according to our data. Variant chr2-120988854-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 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.2889C>T	p.Ser963Ser	synonymous	Exon 14 of 14	NP_001361282.1	A0A7I2PJA1
	GLI2	NM_001371271.1		c.2940C>T	p.Ser980Ser	synonymous	Exon 14 of 14	NP_001358200.1	P10070-5
	GLI2	NM_005270.5		c.2940C>T	p.Ser980Ser	synonymous	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.2889C>T	p.Ser963Ser	synonymous	Exon 14 of 14	ENSP00000354586.5	A0A7I2PJA1
	GLI2	ENST00000452319.6	TSL:5	c.2940C>T	p.Ser980Ser	synonymous	Exon 13 of 13	ENSP00000390436.1	P10070-5
	GLI2	ENST00000934404.1		c.2883C>T	p.Ser961Ser	synonymous	Exon 14 of 14	ENSP00000604463.1

Frequencies

GnomAD3 genomes AF: 0.0435 AC: 6584 AN: 151214 Hom.: 510 Cov.: 33

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.00754

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000532

Gnomad OTH AF: 0.0284

GnomAD2 exomes AF: 0.00561 AC: 630 AN: 112308 AF XY: 0.00434

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.00702

Gnomad ASJ exome AF: 0.00520

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000432

Gnomad OTH exome AF: 0.00575

GnomAD4 exome AF: 0.00411 AC: 5509 AN: 1339606 Hom.: 343 Cov.: 30 AF XY: 0.00362 AC XY: 2392 AN XY: 661220

African (AFR) AF: 0.154 AC: 4229 AN: 27464

American (AMR) AF: 0.00824 AC: 274 AN: 33240

Ashkenazi Jewish (ASJ) AF: 0.00650 AC: 150 AN: 23060

East Asian (EAS) AF: 0.0000650 AC: 2 AN: 30748

South Asian (SAS) AF: 0.000350 AC: 27 AN: 77244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32960

Middle Eastern (MID) AF: 0.00575 AC: 29 AN: 5040

European-Non Finnish (NFE) AF: 0.000220 AC: 232 AN: 1054996

Other (OTH) AF: 0.0103 AC: 566 AN: 54854

GnomAD4 genome AF: 0.0436 AC: 6592 AN: 151318 Hom.: 510 Cov.: 33 AF XY: 0.0418 AC XY: 3088 AN XY: 73956

African (AFR) AF: 0.150 AC: 6220 AN: 41454

American (AMR) AF: 0.0162 AC: 246 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.00754 AC: 26 AN: 3448

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10262

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000532 AC: 36 AN: 67650

Other (OTH) AF: 0.0281 AC: 59 AN: 2100

Alfa AF: 0.0259 Hom.: 42

Asia WGS AF: 0.0140 AC: 45 AN: 3204

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.52
DANN	Benign	0.78
PhyloP100		-1.8
Mutation Taster		=99/1	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: rs146811565; hg19: chr2-121746430;