2-25161587-CGCCGCTGCT-CGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCT

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS1

The NM_000939.4(POMC):c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC(p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 151,774 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000050 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POMC NM_000939.4 inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.649

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000125 (19/151774) while in subpopulation AFR AF= 0.000462 (19/41146). AF 95% confidence interval is 0.000302. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POMC	NM_000939.4	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	inframe_insertion	3/3	ENST00000395826.7
POMC	NM_001035256.3	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	inframe_insertion	4/4
POMC	NM_001319204.2	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	inframe_insertion	4/4
POMC	NM_001319205.2	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	inframe_insertion	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POMC	ENST00000395826.7	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	inframe_insertion	3/3	2	NM_000939.4	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 151774 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000462

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000498 AC: 7 AN: 1406038 Hom.: 0 Cov.: 33 AF XY: 0.00000720 AC XY: 5 AN XY: 694676

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000249

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000125 AC: 19 AN: 151774 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74138

Gnomad4 AFR AF: 0.000462

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10654394; hg19: chr2-25384456;