2-25161587-CGCCGCTGCT-CGCCGCTGCTGCCGCTGCT

Position:

• chr2-25161587-CGCCGCTGCT-CGCCGCTGCTGCCGCTGCT

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMC	NM_000939.4	c.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	3/3	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	4/4		NP_001030333.1
POMC	NM_001319204.2	c.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	4/4		NP_001306133.1
POMC	NM_001319205.2	c.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	3/3		NP_001306134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7	c.289_297dupAGCAGCGGC	p.Gly99_Ala100insSerSerGly	conservative_inframe_insertion	3/3	2	NM_000939.4	ENSP00000379170.2

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

GnomAD3 exomes AF: 0.0564 AC: 8677 AN: 153946 Hom.: 448 AF XY: 0.0554 AC XY: 4629 AN XY: 83598

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 SAS exome AF: 0.0582

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

Gnomad4 AFR exome AF: 0.282

Gnomad4 AMR exome AF: 0.0393

Gnomad4 ASJ exome AF: 0.0950

Gnomad4 EAS exome AF: 0.000741

Gnomad4 SAS exome AF: 0.0602

Gnomad4 FIN exome AF: 0.0575

Gnomad4 NFE exome AF: 0.0558

Gnomad4 OTH exome AF: 0.0681

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

Gnomad4 AFR AF: 0.270

Gnomad4 AMR AF: 0.0554

Gnomad4 ASJ AF: 0.0874

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0591

Gnomad4 FIN AF: 0.0538

Gnomad4 NFE AF: 0.0552

Gnomad4 OTH AF: 0.0907

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 15472174) -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2017	- -

Monogenic Non-Syndromic Obesity Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Obesity due to pro-opiomelanocortin deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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;