2-120984731-C-T

Variant names:

• chr2-120984731-C-T
• rs13008360
• NM_001374353.1:c.1893C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001374353.1(GLI2):​c.1893C>T​(p.Thr631Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0261 in 1,612,710 control chromosomes in the GnomAD database, including 694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (54 hom., cov: 33)
  • Exomes 𝑓: 0.027 (640 hom.)
• Consequence: GLI2 NM_001374353.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.14
• Publications: 7 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=-0.53).
• BP6: Variant 2-120984731-C-T is Benign according to our data. Variant chr2-120984731-C-T is described in ClinVar as Benign. ClinVar VariationId is 259721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0203 (3086/152322) while in subpopulation NFE AF = 0.0292 (1989/68010). AF 95% confidence interval is 0.0282. There are 54 homozygotes in GnomAd4. There are 1591 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 54 AD,AR gene

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.1893C>T	p.Thr631Thr	synonymous	Exon 12 of 14	NP_001361282.1	A0A7I2PJA1
	GLI2	NM_001371271.1		c.1944C>T	p.Thr648Thr	synonymous	Exon 12 of 14	NP_001358200.1	P10070-5
	GLI2	NM_005270.5		c.1944C>T	p.Thr648Thr	synonymous	Exon 12 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.1893C>T	p.Thr631Thr	synonymous	Exon 12 of 14	ENSP00000354586.5	A0A7I2PJA1
	GLI2	ENST00000452319.6	TSL:5	c.1944C>T	p.Thr648Thr	synonymous	Exon 11 of 13	ENSP00000390436.1	P10070-5
	GLI2	ENST00000934404.1		c.1887C>T	p.Thr629Thr	synonymous	Exon 12 of 14	ENSP00000604463.1

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3086 AN: 152204 Hom.: 54 Cov.: 33

Gnomad AFR AF: 0.00506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0500

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0292

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.0235 AC: 5737 AN: 244588 AF XY: 0.0233

Gnomad AFR exome AF: 0.00461

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0536

Gnomad NFE exome AF: 0.0338

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0267 AC: 39044 AN: 1460388 Hom.: 640 Cov.: 33 AF XY: 0.0262 AC XY: 19043 AN XY: 726560

African (AFR) AF: 0.00445 AC: 149 AN: 33464

American (AMR) AF: 0.0102 AC: 456 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0178 AC: 464 AN: 26112

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.00400 AC: 345 AN: 86230

European-Finnish (FIN) AF: 0.0562 AC: 2937 AN: 52296

Middle Eastern (MID) AF: 0.0193 AC: 110 AN: 5708

European-Non Finnish (NFE) AF: 0.0299 AC: 33232 AN: 1111824

Other (OTH) AF: 0.0224 AC: 1349 AN: 60354

GnomAD4 genome AF: 0.0203 AC: 3086 AN: 152322 Hom.: 54 Cov.: 33 AF XY: 0.0214 AC XY: 1591 AN XY: 74486

African (AFR) AF: 0.00505 AC: 210 AN: 41586

American (AMR) AF: 0.0157 AC: 240 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4830

European-Finnish (FIN) AF: 0.0500 AC: 531 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0292 AC: 1989 AN: 68010

Other (OTH) AF: 0.0208 AC: 44 AN: 2116

Alfa AF: 0.0261 Hom.: 111

Bravo AF: 0.0167

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0274

EpiControl AF: 0.0292

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.4
DANN	Benign	0.77
PhyloP100		-4.1
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: rs13008360; hg19: chr2-121742307; COSMIC: COSV58035195;