2-25161587-CGCCGCTGCT-CGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCT

Variant names:

• chr2-25161587-C-CGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCT
• rs10654394
• NM_000939.4:c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000939.4(POMC):​c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC​(p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 151,890 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00015 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POMC NM_000939.4 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.649
• Publications: 11 publications found

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]

POMC Gene-Disease associations (from GenCC):

• obesity due to pro-opiomelanocortin deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
• inherited obesity

  Inheritance: SD, AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	Exon 3 of 3	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	Exon 4 of 4		NP_001030333.1
POMC	NM_001319204.2	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	Exon 4 of 4		NP_001306133.1
POMC	NM_001319205.2	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	Exon 3 of 3		NP_001306134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	Exon 3 of 3	2	NM_000939.4	ENSP00000379170.2

Frequencies

GnomAD3 genomes AF: 0.000152 AC: 23 AN: 151774 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000284 AC: 4 AN: 1406038 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 694676

African (AFR) AF: 0.0000316 AC: 1 AN: 31600

American (AMR) AF: 0.00 AC: 0 AN: 36824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25194

East Asian (EAS) AF: 0.00 AC: 0 AN: 36442

South Asian (SAS) AF: 0.00 AC: 0 AN: 80238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1083400

Other (OTH) AF: 0.0000172 AC: 1 AN: 58262

GnomAD4 genome AF: 0.000151 AC: 23 AN: 151890 Hom.: 1 Cov.: 31 AF XY: 0.000162 AC XY: 12 AN XY: 74264

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

African (AFR) AF: 0.000509 AC: 21 AN: 41268

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67970

Other (OTH) AF: 0.00 AC: 0 AN: 2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000310927), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.65
Mutation Taster		=75/25	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs10654394; hg19: chr2-25384456;