2-25161587-CGCCGCTGCT-CGCCGCTGCTGCCGCTGCT

Variant names:

• chr2-25161587-C-CGCCGCTGCT
• rs10654394
• NM_000939.4:c.289_297dupAGCAGCGGC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000939.4(POMC):​c.289_297dupAGCAGCGGC​(p.Gly99_Ala100insSerSerGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0659 in 1,557,810 control chromosomes in the GnomAD database, including 5,307 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1657 hom., cov: 31)
  • Exomes 𝑓: 0.061 (3650 hom.)
• Consequence: POMC NM_000939.4 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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: 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-25161587-C-CGCCGCTGCT is Benign according to our data. Variant chr2-25161587-C-CGCCGCTGCT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

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_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	Exon 3 of 3	NP_000930.1	P01189
	POMC	NM_001035256.3		c.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	Exon 4 of 4	NP_001030333.1	P01189
	POMC	NM_001319204.2		c.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	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_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	Exon 3 of 3	ENSP00000379170.2	P01189
	POMC	ENST00000405623.5	TSL:1	c.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	Exon 3 of 3	ENSP00000384092.1	P01189
	POMC	ENST00000264708.7	TSL:2	c.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	Exon 4 of 4	ENSP00000264708.3	P01189

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17200 AN: 151752 Hom.: 1655 Cov.: 31

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0555

Gnomad ASJ AF: 0.0874

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0583

Gnomad FIN AF: 0.0538

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.0552

Gnomad OTH AF: 0.0897

GnomAD2 exomes AF: 0.0564 AC: 8677 AN: 153946 AF XY: 0.0554

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.0358

Gnomad ASJ exome AF: 0.0944

Gnomad EAS exome AF: 0.000429

Gnomad FIN exome AF: 0.0543

Gnomad NFE exome AF: 0.0487

Gnomad OTH exome AF: 0.0632

GnomAD4 exome AF: 0.0608 AC: 85424 AN: 1405942 Hom.: 3650 Cov.: 33 AF XY: 0.0600 AC XY: 41686 AN XY: 694622

African (AFR) AF: 0.282 AC: 8910 AN: 31572

American (AMR) AF: 0.0393 AC: 1447 AN: 36820

Ashkenazi Jewish (ASJ) AF: 0.0950 AC: 2394 AN: 25194

East Asian (EAS) AF: 0.000741 AC: 27 AN: 36442

South Asian (SAS) AF: 0.0602 AC: 4831 AN: 80230

European-Finnish (FIN) AF: 0.0575 AC: 2784 AN: 48386

Middle Eastern (MID) AF: 0.108 AC: 611 AN: 5680

European-Non Finnish (NFE) AF: 0.0558 AC: 60450 AN: 1083360

Other (OTH) AF: 0.0681 AC: 3970 AN: 58258

GnomAD4 genome AF: 0.113 AC: 17220 AN: 151868 Hom.: 1657 Cov.: 31 AF XY: 0.111 AC XY: 8251 AN XY: 74252

African (AFR) AF: 0.270 AC: 11141 AN: 41252

American (AMR) AF: 0.0554 AC: 846 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0874 AC: 303 AN: 3466

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5158

South Asian (SAS) AF: 0.0591 AC: 285 AN: 4822

European-Finnish (FIN) AF: 0.0538 AC: 571 AN: 10616

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0552 AC: 3750 AN: 67964

Other (OTH) AF: 0.0907 AC: 191 AN: 2106

Alfa AF: 0.0390 Hom.: 42

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Monogenic Non-Syndromic Obesity (1)
-	-	1	Obesity due to pro-opiomelanocortin deficiency (1)

Computational scores

Source: dbNSFP v4.9

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

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; COSMIC: COSV53034322; COSMIC: COSV53034322;