1-234609263-A-G

Position:

• chr1-234609263-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182972.3(IRF2BP2):​c.232T>C​(p.Ser78Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 1,377,458 control chromosomes in the GnomAD database, including 352,861 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41039 hom., cov: 32)
  • Exomes 𝑓: 0.71 (311822 hom.)
• Consequence: IRF2BP2 NM_182972.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.495

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3392341E-6).
• BP6: Variant 1-234609263-A-G is Benign according to our data. Variant chr1-234609263-A-G is described in ClinVar as [Benign]. Clinvar id is 402984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF2BP2	NM_182972.3	c.232T>C	p.Ser78Pro	missense_variant	1/2	ENST00000366609.4	NP_892017.2
IRF2BP2	NM_001077397.1	c.232T>C	p.Ser78Pro	missense_variant	1/2		NP_001070865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF2BP2	ENST00000366609.4	c.232T>C	p.Ser78Pro	missense_variant	1/2	1	NM_182972.3	ENSP00000355568	P3
IRF2BP2	ENST00000366610.7	c.232T>C	p.Ser78Pro	missense_variant	1/2	1		ENSP00000355569	A1
	ENST00000436039.1	n.631-158A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.728 AC: 109668 AN: 150662 Hom.: 41000 Cov.: 32

Gnomad AFR AF: 0.842

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.749

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.734

GnomAD3 exomes AF: 0.610 AC: 11605 AN: 19032 Hom.: 3855 AF XY: 0.611 AC XY: 6810 AN XY: 11144

Gnomad AFR exome AF: 0.760

Gnomad AMR exome AF: 0.379

Gnomad ASJ exome AF: 0.701

Gnomad EAS exome AF: 0.178

Gnomad SAS exome AF: 0.457

Gnomad FIN exome AF: 0.725

Gnomad NFE exome AF: 0.696

Gnomad OTH exome AF: 0.666

GnomAD4 exome AF: 0.707 AC: 867342 AN: 1226686 Hom.: 311822 Cov.: 64 AF XY: 0.702 AC XY: 420732 AN XY: 599294

Gnomad4 AFR exome AF: 0.840

Gnomad4 AMR exome AF: 0.517

Gnomad4 ASJ exome AF: 0.746

Gnomad4 EAS exome AF: 0.278

Gnomad4 SAS exome AF: 0.499

Gnomad4 FIN exome AF: 0.718

Gnomad4 NFE exome AF: 0.729

Gnomad4 OTH exome AF: 0.691

GnomAD4 genome AF: 0.728 AC: 109756 AN: 150772 Hom.: 41039 Cov.: 32 AF XY: 0.718 AC XY: 52866 AN XY: 73584

Gnomad4 AFR AF: 0.842

Gnomad4 AMR AF: 0.621

Gnomad4 ASJ AF: 0.749

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.488

Gnomad4 FIN AF: 0.715

Gnomad4 NFE AF: 0.735

Gnomad4 OTH AF: 0.730

Alfa AF: 0.732 Hom.: 4724

Bravo AF: 0.723

ExAC AF: 0.361 AC: 11334

Asia WGS AF: 0.416 AC: 1389 AN: 3326

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	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 -
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 72% of patients studied by a panel of primary immunodeficiencies. Number of patients: 68. Only high quality variants are reported. -

not provided Benign:2

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

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
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.2
DANN	Benign	0.13
DEOGEN2	Benign	0.0037	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.17	T;T
MetaRNN	Benign	0.0000013	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	1.8	N;N
REVEL	Benign	0.028
Sift	Benign	1.0	T;T
Sift4G	Benign	0.95	T;T
Polyphen		0.0	B;B
Vest4		0.048
MPC		1.5
ClinPred		0.0033	T
GERP RS		0.22
Varity_R		0.099
gMVP		0.15

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: rs7545855; hg19: chr1-234745009; COSMIC: COSV64014804; COSMIC: COSV64014804;