chr2-120986307-G-A

Variant names:

• chr2-120986307-G-A
• rs114259687
• NM_001374353.1:c.1935G>A

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.1935G>A​(p.Ser645Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,613,374 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (23 hom.)
• Consequence: GLI2 NM_001374353.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.10
• Publications: 1 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=-0.88).
• BP6: Variant 2-120986307-G-A is Benign according to our data. Variant chr2-120986307-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00219 (334/152346) while in subpopulation SAS AF = 0.0104 (50/4830). AF 95% confidence interval is 0.00807. There are 1 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 23 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.1935G>A	p.Ser645Ser	synonymous	Exon 13 of 14	NP_001361282.1	A0A7I2PJA1
	GLI2	NM_001371271.1		c.1986G>A	p.Ser662Ser	synonymous	Exon 13 of 14	NP_001358200.1	P10070-5
	GLI2	NM_005270.5		c.1986G>A	p.Ser662Ser	synonymous	Exon 13 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.1935G>A	p.Ser645Ser	synonymous	Exon 13 of 14	ENSP00000354586.5	A0A7I2PJA1
	GLI2	ENST00000452319.6	TSL:5	c.1986G>A	p.Ser662Ser	synonymous	Exon 12 of 13	ENSP00000390436.1	P10070-5
	GLI2	ENST00000934404.1		c.1929G>A	p.Ser643Ser	synonymous	Exon 13 of 14	ENSP00000604463.1

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00348 AC: 860 AN: 247116 AF XY: 0.00422

Gnomad AFR exome AF: 0.0000634

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00290

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00334

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00279 AC: 4073 AN: 1461028 Hom.: 23 Cov.: 33 AF XY: 0.00317 AC XY: 2305 AN XY: 726858

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.00322 AC: 144 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 71 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0110 AC: 953 AN: 86258

European-Finnish (FIN) AF: 0.000361 AC: 19 AN: 52588

Middle Eastern (MID) AF: 0.0154 AC: 89 AN: 5768

European-Non Finnish (NFE) AF: 0.00229 AC: 2551 AN: 1111986

Other (OTH) AF: 0.00387 AC: 234 AN: 60390

GnomAD4 genome AF: 0.00219 AC: 334 AN: 152346 Hom.: 1 Cov.: 33 AF XY: 0.00232 AC XY: 173 AN XY: 74498

African (AFR) AF: 0.000457 AC: 19 AN: 41586

American (AMR) AF: 0.00327 AC: 50 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4830

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10630

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 68030

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00270 Hom.: 1

Bravo AF: 0.00250

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00587

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Holoprosencephaly 9;C4014479:Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome (2)
-	-	2	not specified (2)
-	-	1	GLI2-related disorder (1)
-	-	1	Holoprosencephaly 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.34
DANN	Benign	0.75
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism

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: rs114259687; hg19: chr2-121743883; COSMIC: COSV58035386;