2-213056961-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001387220.1(IKZF2):c.278A>G(p.Asn93Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,613,838 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0073 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (52 hom.)
• Consequence: IKZF2 NM_001387220.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.67

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036978126).
• BP6: Variant 2-213056961-T-C is Benign according to our data. Variant chr2-213056961-T-C is described in ClinVar as [Benign]. Clinvar id is 786765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00608 (8887/1461708) while in subpopulation MID AF= 0.0231 (133/5768). AF 95% confidence interval is 0.0199. There are 52 homozygotes in gnomad4_exome. There are 4625 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IKZF2	NM_001387220.1	c.278A>G	p.Asn93Ser	missense_variant	5/9	ENST00000434687.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IKZF2	ENST00000434687.6	c.278A>G	p.Asn93Ser	missense_variant	5/9	5	NM_001387220.1	P4

Frequencies

GnomAD3 genomes AF: 0.00730 AC: 1109 AN: 152012 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00610

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00368

Gnomad SAS AF: 0.00995

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00604

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00637 AC: 1599 AN: 250986 Hom.: 13 AF XY: 0.00686 AC XY: 931 AN XY: 135624

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.00417

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.00430

Gnomad SAS exome AF: 0.0105

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00590

Gnomad OTH exome AF: 0.00687

GnomAD4 exome AF: 0.00608 AC: 8887 AN: 1461708 Hom.: 52 Cov.: 31 AF XY: 0.00636 AC XY: 4625 AN XY: 727144

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.00445

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.00645

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.00185

Gnomad4 NFE exome AF: 0.00549

Gnomad4 OTH exome AF: 0.00780

GnomAD4 genome AF: 0.00732 AC: 1113 AN: 152130 Hom.: 11 Cov.: 32 AF XY: 0.00686 AC XY: 510 AN XY: 74374

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.00603

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00369

Gnomad4 SAS AF: 0.00955

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00605

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00719 Hom.: 10

Bravo AF: 0.00768

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.00709 AC: 61

ExAC AF: 0.00643 AC: 781

Asia WGS AF: 0.0150 AC: 51 AN: 3478

EpiCase AF: 0.00895

EpiControl AF: 0.00830

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	IKZF2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 01, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	16
Dann	Benign	0.69
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
MetaRNN	Benign	0.0037	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.47	T
REVEL	Benign	0.052
Sift4G	Benign	0.34	T;T;T;T;T;.
Polyphen		0.0040, 0.0030	.;.;.;B;B;.
Vest4		0.19
MVP		0.082
MPC		0.0087
ClinPred		0.0039	T
GERP RS		4.9
Varity_R		0.024
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs16849611; hg19: chr2-213921685;