chr2-25161090-C-T
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7
The NM_000939.4(POMC):c.795G>A(p.Lys265=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,830 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 1 hom. )
Consequence
POMC
NM_000939.4 synonymous
NM_000939.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.482
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 Likely_benign. Variant got -4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
Variant 2-25161090-C-T is Benign according to our data. Variant chr2-25161090-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3030401.Status of the report is no_assertion_criteria_provided, 0 stars.
BP7
Synonymous conserved (PhyloP=0.482 with no splicing effect.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| POMC | NM_000939.4 | c.795G>A | p.Lys265= | synonymous_variant | 3/3 | ENST00000395826.7 | NP_000930.1 | |
| POMC | NM_001035256.3 | c.795G>A | p.Lys265= | synonymous_variant | 4/4 | NP_001030333.1 | ||
| POMC | NM_001319204.2 | c.795G>A | p.Lys265= | synonymous_variant | 4/4 | NP_001306133.1 | ||
| POMC | NM_001319205.2 | c.795G>A | p.Lys265= | synonymous_variant | 3/3 | NP_001306134.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| POMC | ENST00000395826.7 | c.795G>A | p.Lys265= | synonymous_variant | 3/3 | 2 | NM_000939.4 | ENSP00000379170 | P1 | |
| POMC | ENST00000405623.5 | c.795G>A | p.Lys265= | synonymous_variant | 3/3 | 1 | ENSP00000384092 | P1 | ||
| POMC | ENST00000264708.7 | c.795G>A | p.Lys265= | synonymous_variant | 4/4 | 2 | ENSP00000264708 | P1 | ||
| POMC | ENST00000380794.5 | c.795G>A | p.Lys265= | synonymous_variant | 4/4 | 2 | ENSP00000370171 | P1 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152018Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251120Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135818
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GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461812Hom.: 1 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727222
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GnomAD4 genome 0.0000197 AC: 3AN: 152018Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74226
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
POMC-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 17, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Benign
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DANN
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at