1-234608504-G-C

Position:

• chr1-234608504-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000366609.4(IRF2BP2):​c.991C>G​(p.Leu331Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000961 in 1,456,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L331L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: IRF2BP2 ENST00000366609.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.511

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1591003).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF2BP2	NM_182972.3	c.991C>G	p.Leu331Val	missense_variant	1/2	ENST00000366609.4	NP_892017.2
IRF2BP2	NM_001077397.1	c.991C>G	p.Leu331Val	missense_variant	1/2		NP_001070865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF2BP2	ENST00000366609.4	c.991C>G	p.Leu331Val	missense_variant	1/2	1	NM_182972.3	ENSP00000355568	P3
IRF2BP2	ENST00000366610.7	c.991C>G	p.Leu331Val	missense_variant	1/2	1		ENSP00000355569	A1
	ENST00000436039.1	n.630+867G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000961 AC: 14 AN: 1456608 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 724294

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000382

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2022

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 331 of the IRF2BP2 protein (p.Leu331Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1466746). This variant has not been reported in the literature in individuals affected with IRF2BP2-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.032
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.95	P;P
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.050
Sift	Uncertain	0.017	D;D
Sift4G	Benign	0.20	T;T
Polyphen		0.26	B;B
Vest4		0.23
MutPred		0.066		Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);
MVP		0.55
MPC		0.46
ClinPred		0.66	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.23
gMVP		0.24

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: rs8722; hg19: chr1-234744250;