rs2656052

Variant names:

• chr15-78448590-A-C
• rs2656052
• NM_004136.4:c.106+8709A>C

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+8709A>C 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 152,140 control chromosomes in the GnomAD database, including 10,113 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 (10113 hom., cov: 33)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.932
• Publications: 19 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.106+8709A>C		intron_variant	Intron 2 of 21	ENST00000258886.13	NP_004127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.106+8709A>C		intron_variant	Intron 2 of 21	1	NM_004136.4	ENSP00000258886.8

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54386 AN: 152022 Hom.: 10106 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: 0.159

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: 54435 AN: 152140 Hom.: 10113 Cov.: 33 AF XY: 0.352 AC XY: 26216 AN XY: 74382

African (AFR) AF: 0.441 AC: 18279 AN: 41482

American (AMR) AF: 0.308 AC: 4711 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1329 AN: 3470

East Asian (EAS) AF: 0.160 AC: 829 AN: 5180

South Asian (SAS) AF: 0.237 AC: 1144 AN: 4832

European-Finnish (FIN) AF: 0.317 AC: 3355 AN: 10588

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

European-Non Finnish (NFE) AF: 0.347 AC: 23595 AN: 67976

Other (OTH) AF: 0.345 AC: 731 AN: 2116

Alfa AF: 0.348 Hom.: 4215

Bravo AF: 0.361

Asia WGS AF: 0.219 AC: 765 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.7
DANN	Benign	0.59
PhyloP100		0.93
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: rs2656052; hg19: chr15-78740932;