22-50486669-G-C

Variant names:

• chr22-50486669-G-C
• rs2232873
• NM_017584.6:c.-229G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017584.6(MIOX):​c.-229G>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 471,902 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MIOX NM_017584.6 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 0 publications found

Genes affected

MIOX (HGNC:14522): (myo-inositol oxygenase) Enables ferric iron binding activity and inositol oxygenase activity. Involved in inositol catabolic process. Predicted to be located in cytoplasm and inclusion body. [provided by Alliance of Genome Resources, Apr 2022]

ADM2 (HGNC:28898): (adrenomedullin 2) This gene encodes a member of the calcitonin gene-related peptide (CGRP)/calcitonin family of hormones that play a role in the regulation of cardiovascular homeostasis, prolactin release, anti-diuresis, anti-natriuresis, and regulation of food and water intake. The encoded protein is proteolytically processed to generate one or more biologically active peptides. [provided by RefSeq, Jul 2015]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIOX	NM_017584.6	c.-229G>C		upstream_gene_variant		ENST00000216075.11	NP_060054.4
ADM2	NM_001253845.2	c.*3766G>C		downstream_gene_variant		ENST00000395737.2	NP_001240774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIOX	ENST00000216075.11	c.-229G>C		upstream_gene_variant		1	NM_017584.6	ENSP00000216075.6
ADM2	ENST00000395737.2	c.*3766G>C		downstream_gene_variant		1	NM_001253845.2	ENSP00000379086.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000212 AC: 1 AN: 471902 Hom.: 0 AF XY: 0.00000399 AC XY: 1 AN XY: 250334

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 13374

American (AMR) AF: 0.00 AC: 0 AN: 25062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14682

East Asian (EAS) AF: 0.00 AC: 0 AN: 30872

South Asian (SAS) AF: 0.00 AC: 0 AN: 49928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2358

European-Non Finnish (NFE) AF: 0.00000358 AC: 1 AN: 279464

Other (OTH) AF: 0.00 AC: 0 AN: 26696

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.30
DANN	Benign	0.68
PhyloP100		-1.1
PromoterAI		-0.0090	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2232873; hg19: chr22-50925098;