chr2-25161587-CGCCGCTGCT-C

Variant names:

• chr2-25161587-CGCCGCTGCT-C
• rs10654394
• NM_000939.4:c.289_297delAGCAGCGGC

Variant summary

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

The NM_000939.4(POMC):​c.289_297delAGCAGCGGC​(p.Ser97_Gly99del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000424 in 1,557,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: POMC NM_000939.4 conservative_inframe_deletion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.32
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• inherited obesity

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

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000939.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	NM_000939.4	MANE Select	c.289_297delAGCAGCGGC	p.Ser97_Gly99del	conservative_inframe_deletion	Exon 3 of 3	NP_000930.1	P01189
	POMC	NM_001035256.3		c.289_297delAGCAGCGGC	p.Ser97_Gly99del	conservative_inframe_deletion	Exon 4 of 4	NP_001030333.1	P01189
	POMC	NM_001319204.2		c.289_297delAGCAGCGGC	p.Ser97_Gly99del	conservative_inframe_deletion	Exon 4 of 4	NP_001306133.1	P01189

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	ENST00000395826.7	TSL:2 MANE Select	c.289_297delAGCAGCGGC	p.Ser97_Gly99del	conservative_inframe_deletion	Exon 3 of 3	ENSP00000379170.2	P01189
	POMC	ENST00000405623.5	TSL:1	c.289_297delAGCAGCGGC	p.Ser97_Gly99del	conservative_inframe_deletion	Exon 3 of 3	ENSP00000384092.1	P01189
	POMC	ENST00000264708.7	TSL:2	c.289_297delAGCAGCGGC	p.Ser97_Gly99del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000264708.3	P01189

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151776 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000729

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000390 AC: 6 AN: 153946 AF XY: 0.0000239

Gnomad AFR exome AF: 0.000146

Gnomad AMR exome AF: 0.0000393

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000859

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000343

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.0000420 AC: 59 AN: 1406036 Hom.: 0 AF XY: 0.0000432 AC XY: 30 AN XY: 694674

African (AFR) AF: 0.0000949 AC: 3 AN: 31600

American (AMR) AF: 0.0000543 AC: 2 AN: 36824

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25194

East Asian (EAS) AF: 0.0000549 AC: 2 AN: 36442

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80238

European-Finnish (FIN) AF: 0.0000413 AC: 2 AN: 48392

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

European-Non Finnish (NFE) AF: 0.0000415 AC: 45 AN: 1083400

Other (OTH) AF: 0.0000515 AC: 3 AN: 58262

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151776 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74138

African (AFR) AF: 0.0000729 AC: 3 AN: 41148

American (AMR) AF: 0.00 AC: 0 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000120 Hom.: 42

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	POMC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=181/19	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;