2-25161587-CGCCGCTGCT-CGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCT

Position:

chr2-25161587-CGCCGCTGCT-CGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCTGCCGCTGCT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_000939.4(POMC):c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC(p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 151,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POMC
NM_000939.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.649

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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 = 0.000145 (22/151892) while in subpopulation AFR AF= 0.000485 (20/41270). AF 95% confidence interval is 0.000321. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMC	NM_000939.4 link	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	3/3	ENST00000395826.7	NP_000930.1	P01189
POMC	NM_001035256.3 link	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	4/4		NP_001030333.1	P01189
POMC	NM_001319204.2 link	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	4/4		NP_001306133.1	P01189
POMC	NM_001319205.2 link	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	3/3		NP_001306134.1	P01189

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7 link	c.297_298insAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGCAGCAGCGGC	p.Gly99_Ala100insSerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGlySerSerGly	conservative_inframe_insertion	3/3	2	NM_000939.4	ENSP00000379170.2		P01189

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

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:

AN:

1406038

Hom.:

Cov.:

AF XY:

0.00000576

AC XY:

AN XY:

694676

show subpopulations

Gnomad4 AFR exome

AF:

0.000127

Gnomad4 AMR exome

AF:

0.0000543

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:

0.00

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.000145

AC:

AN:

151892

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.000485

Gnomad4 AMR

AF:

0.0000654

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 23, 2022

This variant, c.297_298ins90, results in the insertion of 30 amino acid(s) of the POMC protein (p.Gly99_Ala100ins30), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POMC-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over