NM_004136.4:c.2596-968G>C

Variant names:

• chr15-78496158-G-C
• rs11636431
• NM_004136.4:c.2596-968G>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.2596-968G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 152,138 control chromosomes in the GnomAD database, including 3,956 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 0.21 (3956 hom., cov: 32)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29
• Publications: 8 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.2596-968G>C		intron_variant	Intron 20 of 21	ENST00000258886.13	NP_004127.2
IREB2	NM_001320942.2	c.2425-968G>C		intron_variant	Intron 20 of 21		NP_001307871.2
IREB2	NM_001354994.2	c.2425-968G>C		intron_variant	Intron 20 of 21		NP_001341923.2
IREB2	NM_001320941.2	c.1846-968G>C		intron_variant	Intron 19 of 20		NP_001307870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.2596-968G>C		intron_variant	Intron 20 of 21	1	NM_004136.4	ENSP00000258886.8
IREB2	ENST00000558570.5	n.*1863-968G>C		intron_variant	Intron 19 of 20	1		ENSP00000454063.1
IREB2	ENST00000559091.1	c.55-968G>C		intron_variant	Intron 1 of 1	3		ENSP00000453863.1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31319 AN: 152020 Hom.: 3953 Cov.: 32

Gnomad AFR AF: 0.0581

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.203

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

GnomAD4 genome AF: 0.206 AC: 31302 AN: 152138 Hom.: 3956 Cov.: 32 AF XY: 0.208 AC XY: 15479 AN XY: 74356

African (AFR) AF: 0.0580 AC: 2407 AN: 41508

American (AMR) AF: 0.212 AC: 3245 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 687 AN: 3470

East Asian (EAS) AF: 0.328 AC: 1697 AN: 5178

South Asian (SAS) AF: 0.245 AC: 1181 AN: 4818

European-Finnish (FIN) AF: 0.268 AC: 2827 AN: 10564

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18499 AN: 68006

Other (OTH) AF: 0.200 AC: 422 AN: 2114

Alfa AF: 0.132 Hom.: 268

Bravo AF: 0.198

Asia WGS AF: 0.231 AC: 804 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.028
DANN	Benign	0.75
PhyloP100		-1.3
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: rs11636431; hg19: chr15-78788500;