rs2568494

Variant names:

• chr15-78448622-G-A
• rs2568494
• NM_004136.4:c.106+8741G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004136.4(IREB2):​c.106+8741G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 152,064 control chromosomes in the GnomAD database, including 10,112 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (10112 hom., cov: 33)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 53 publications found

Genes affected

IREB2 (HGNC:6115): (iron responsive element binding protein 2) The protein encoded by this gene is an RNA-binding protein that acts to regulate iron levels in the cells by regulating the translation and stability of mRNAs that affect iron homeostasis under conditions when iron is depleted. When iron levels are low, this protein binds to iron-responsive elements (IRES), stem-loop structures located either in the 5' or 3' UTRs. Binding to the 5' UTR represses translation, while binding to the 3' UTR inhibits mRNA degradation. When iron is found in the cell, this protein is degraded in a F-box and leucine rich repeat protein 5-dependent manner. Variants in this gene have been associated with lung cancer and chronic obstructive pulmonary disease (COPD). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]

IREB2 Gene-Disease associations (from GenCC):

• neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004136.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	NM_004136.4	MANE Select	c.106+8741G>A		intron	N/A	NP_004127.2
	IREB2	NM_001320942.2		c.-66+8741G>A		intron	N/A	NP_001307871.2
	IREB2	NM_001354994.2		c.-66+8741G>A		intron	N/A	NP_001341923.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	ENST00000258886.13	TSL:1 MANE Select	c.106+8741G>A		intron	N/A	ENSP00000258886.8
	IREB2	ENST00000560440.5	TSL:1	c.106+8741G>A		intron	N/A	ENSP00000452938.1
	IREB2	ENST00000558570.5	TSL:1	n.106+8741G>A		intron	N/A	ENSP00000454063.1

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54366 AN: 151944 Hom.: 10105 Cov.: 33

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.348

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.358 AC: 54415 AN: 152064 Hom.: 10112 Cov.: 33 AF XY: 0.353 AC XY: 26222 AN XY: 74342

African (AFR) AF: 0.440 AC: 18263 AN: 41464

American (AMR) AF: 0.308 AC: 4709 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1330 AN: 3472

East Asian (EAS) AF: 0.161 AC: 831 AN: 5172

South Asian (SAS) AF: 0.237 AC: 1141 AN: 4822

European-Finnish (FIN) AF: 0.317 AC: 3357 AN: 10576

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23593 AN: 67960

Other (OTH) AF: 0.345 AC: 729 AN: 2110

Alfa AF: 0.352 Hom.: 12450

Bravo AF: 0.361

Asia WGS AF: 0.219 AC: 765 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.2
DANN	Benign	0.38
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs2568494; hg19: chr15-78740964;