2-25164752-G-GCCACCCGAGGGGCCCCCGAGGGCCC

Position:

• chr2-25164752-G-GCCACCCGAGGGGCCCCCGAGGGCCC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000939.4(POMC):​c.20_21insGGGCCCTCGGGGGCCCCTCGGGTGG​(p.Ser7fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POMC NM_000939.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.13

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_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-25164752-G-GCCACCCGAGGGGCCCCCGAGGGCCC is Pathogenic according to our data. Variant chr2-25164752-G-GCCACCCGAGGGGCCCCCGAGGGCCC is described in ClinVar as [Pathogenic]. Clinvar id is 520619.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMC	NM_000939.4	c.20_21insGGGCCCTCGGGGGCCCCTCGGGTGG	p.Ser7fs	frameshift_variant	2/3	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.20_21insGGGCCCTCGGGGGCCCCTCGGGTGG	p.Ser7fs	frameshift_variant	3/4		NP_001030333.1
POMC	NM_001319204.2	c.20_21insGGGCCCTCGGGGGCCCCTCGGGTGG	p.Ser7fs	frameshift_variant	3/4		NP_001306133.1
POMC	NM_001319205.2	c.20_21insGGGCCCTCGGGGGCCCCTCGGGTGG	p.Ser7fs	frameshift_variant	2/3		NP_001306134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7	c.20_21insGGGCCCTCGGGGGCCCCTCGGGTGG	p.Ser7fs	frameshift_variant	2/3	2	NM_000939.4	ENSP00000379170.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251020 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135794

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000684 AC: 10 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2014

- -

POMC-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 07, 2024

The POMC c.20_21insGGGCCCTCGGGGGCCCCTCGGGTGG variant is predicted to result in a frameshift and premature protein termination (p.Ser7Argfs*120). This variant was reported in the homozygous state in an individual with obesity, ACTH deficiency, hypothyroidism, language delay, and motor delays (Hilado and Randhawa. 2018. PubMed ID: 29858905). This variant has also been reported in the homozygous state in one individual with epilepsy (Helbig et al. 2016. PubMed ID: 26795593). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in POMC are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

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: rs746815510; hg19: chr2-25387621;