2-25163195-A-G

Position:

• chr2-25163195-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000939.4(POMC):​c.133-1443T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 152,160 control chromosomes in the GnomAD database, including 3,919 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (3919 hom., cov: 32)
• Consequence: POMC NM_000939.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.77

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMC	NM_000939.4	c.133-1443T>C		intron_variant		ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.133-1443T>C		intron_variant			NP_001030333.1
POMC	NM_001319204.2	c.133-1443T>C		intron_variant			NP_001306133.1
POMC	NM_001319205.2	c.133-1443T>C		intron_variant			NP_001306134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7	c.133-1443T>C		intron_variant		2	NM_000939.4	ENSP00000379170	P1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28476 AN: 152042 Hom.: 3913 Cov.: 32

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.0483

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.0667

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.152

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.187 AC: 28508 AN: 152160 Hom.: 3919 Cov.: 32 AF XY: 0.185 AC XY: 13740 AN XY: 74418

Gnomad4 AFR AF: 0.396

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.0482

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.0667

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.152

Alfa AF: 0.125 Hom.: 1511

Bravo AF: 0.201

Asia WGS AF: 0.141 AC: 490 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs7565877; hg19: chr2-25386064;