1-234608667-C-A

Position:

• chr1-234608667-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182972.3(IRF2BP2):​c.828G>T​(p.Ala276=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,521,876 control chromosomes in the GnomAD database, including 94,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7665 hom., cov: 33)
  • Exomes 𝑓: 0.35 (86978 hom.)
• Consequence: IRF2BP2 NM_182972.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.425

Genes affected

IRF2BP2 (HGNC:21729): (interferon regulatory factor 2 binding protein 2) This gene encodes an interferon regulatory factor-2 (IRF2) binding protein that interacts with the C-terminal transcriptional repression domain of IRF2. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-234608667-C-A is Benign according to our data. Variant chr1-234608667-C-A is described in ClinVar as [Benign]. Clinvar id is 402983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.425 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF2BP2	NM_182972.3	c.828G>T	p.Ala276=	synonymous_variant	1/2	ENST00000366609.4	NP_892017.2
IRF2BP2	NM_001077397.1	c.828G>T	p.Ala276=	synonymous_variant	1/2		NP_001070865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF2BP2	ENST00000366609.4	c.828G>T	p.Ala276=	synonymous_variant	1/2	1	NM_182972.3	ENSP00000355568	P3
IRF2BP2	ENST00000366610.7	c.828G>T	p.Ala276=	synonymous_variant	1/2	1		ENSP00000355569	A1
	ENST00000436039.1	n.631-754C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46099 AN: 152042 Hom.: 7666 Cov.: 33

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.363

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.332

GnomAD3 exomes AF: 0.356 AC: 46831 AN: 131388 Hom.: 8469 AF XY: 0.358 AC XY: 26743 AN XY: 74636

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.436

Gnomad EAS exome AF: 0.257

Gnomad SAS exome AF: 0.298

Gnomad FIN exome AF: 0.393

Gnomad NFE exome AF: 0.401

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.352 AC: 482618 AN: 1369716 Hom.: 86978 Cov.: 37 AF XY: 0.351 AC XY: 237540 AN XY: 677110

Gnomad4 AFR exome AF: 0.175

Gnomad4 AMR exome AF: 0.299

Gnomad4 ASJ exome AF: 0.419

Gnomad4 EAS exome AF: 0.243

Gnomad4 SAS exome AF: 0.282

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.365

Gnomad4 OTH exome AF: 0.349

GnomAD4 genome AF: 0.303 AC: 46106 AN: 152160 Hom.: 7665 Cov.: 33 AF XY: 0.305 AC XY: 22683 AN XY: 74380

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.334

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.267

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.332

Alfa AF: 0.334 Hom.: 1574

Bravo AF: 0.297

Asia WGS AF: 0.247 AC: 860 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 47% of patients studied by a panel of primary immunodeficiencies. Number of patients: 45. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Immunodeficiency, common variable, 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.6
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4636; hg19: chr1-234744413; COSMIC: COSV64014518; COSMIC: COSV64014518;