chr2-25161236-CCTT-C
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_000939.4(POMC):c.646_648del(p.Lys216del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,460,594 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
POMC
NM_000939.4 inframe_deletion
NM_000939.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.52
Genes affected
POMC (HGNC:9201): (proopiomelanocortin) This gene encodes a preproprotein that undergoes extensive, tissue-specific, post-translational processing via cleavage by subtilisin-like enzymes known as prohormone convertases. There are eight potential cleavage sites within the preproprotein and, depending on tissue type and the available convertases, processing may yield as many as ten biologically active peptides involved in diverse cellular functions. The encoded protein is synthesized mainly in corticotroph cells of the anterior pituitary where four cleavage sites are used; adrenocorticotrophin, essential for normal steroidogenesis and the maintenance of normal adrenal weight, and lipotropin beta are the major end products. In other tissues, including the hypothalamus, placenta, and epithelium, all cleavage sites may be used, giving rise to peptides with roles in pain and energy homeostasis, melanocyte stimulation, and immune modulation. These include several distinct melanotropins, lipotropins, and endorphins that are contained within the adrenocorticotrophin and beta-lipotropin peptides. The antimicrobial melanotropin alpha peptide exhibits antibacterial and antifungal activity. Mutations in this gene have been associated with early onset obesity, adrenal insufficiency, and red hair pigmentation. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000939.4. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POMC | NM_000939.4 | c.646_648del | p.Lys216del | inframe_deletion | 3/3 | ENST00000395826.7 | |
POMC | NM_001035256.3 | c.646_648del | p.Lys216del | inframe_deletion | 4/4 | ||
POMC | NM_001319204.2 | c.646_648del | p.Lys216del | inframe_deletion | 4/4 | ||
POMC | NM_001319205.2 | c.646_648del | p.Lys216del | inframe_deletion | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POMC | ENST00000395826.7 | c.646_648del | p.Lys216del | inframe_deletion | 3/3 | 2 | NM_000939.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
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GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249650Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135154
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GnomAD4 exome AF: 0.00000822 AC: 12AN: 1460594Hom.: 0 AF XY: 0.00000688 AC XY: 5AN XY: 726478
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
POMC-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 09, 2024 | The POMC c.646_648delAAG variant is predicted to result in an in-frame deletion (p.Lys216del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0047% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at