chr2-213007389-T-C

Variant names:

• chr2-213007389-T-C
• NM_001387220.1:c.1552A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001387220.1(IKZF2):​c.1552A>G​(p.Ile518Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IKZF2 NM_001387220.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

IKZF2 (HGNC:13177): (IKAROS family zinc finger 2) This gene encodes a member of the Ikaros family of zinc-finger proteins. Three members of this protein family (Ikaros, Aiolos and Helios) are hematopoietic-specific transcription factors involved in the regulation of lymphocyte development. This protein forms homo- or hetero-dimers with other Ikaros family members, and is thought to function predominantly in early hematopoietic development. Multiple transcript variants encoding different isoforms have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

IKZF2 Gene-Disease associations (from GenCC):

• HELIOS deficiency

  Inheritance: SD, AR Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• hearing loss disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• immunodeficiency disease

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000273118 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IKZF2	NM_001387220.1	c.1552A>G	p.Ile518Val	missense_variant	Exon 9 of 9	ENST00000434687.6	NP_001374149.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IKZF2	ENST00000434687.6	c.1552A>G	p.Ile518Val	missense_variant	Exon 9 of 9	5	NM_001387220.1	ENSP00000412869.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1552A>G (p.I518V) alteration is located in exon 8 (coding exon 7) of the IKZF2 gene. This alteration results from a A to G substitution at nucleotide position 1552, causing the isoleucine (I) at amino acid position 518 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;.;.;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.49	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	.;.;.;M;.
PhyloP100		8.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.85	.;.;N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0070	.;.;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.93, 1.0	.;.;.;P;D
Vest4		0.61
MutPred		0.74		.;.;.;Gain of methylation at R520 (P = 0.0841);.;
MVP		0.47
MPC		0.77
ClinPred		0.94	D
GERP RS		5.7
Varity_R		0.25
gMVP		0.43
Mutation Taster		=68/32	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

hg19: chr2-213872113;