2-25161964-T-C

Variant names:

• chr2-25161964-T-C
• rs6713532
• NM_000939.4:c.133-212A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000939.4(POMC):​c.133-212A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 152,052 control chromosomes in the GnomAD database, including 11,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.36 (11111 hom., cov: 32)
• Consequence: POMC NM_000939.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0540
• Publications: 26 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
• inherited obesity

  Inheritance: SD, AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 2-25161964-T-C is Benign according to our data. Variant chr2-25161964-T-C is described in ClinVar as Benign. ClinVar VariationId is 1279683.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.579 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	NM_000939.4	MANE Select	c.133-212A>G		intron	N/A	NP_000930.1
	POMC	NM_001035256.3		c.133-212A>G		intron	N/A	NP_001030333.1
	POMC	NM_001319204.2		c.133-212A>G		intron	N/A	NP_001306133.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	ENST00000395826.7	TSL:2 MANE Select	c.133-212A>G		intron	N/A	ENSP00000379170.2
	POMC	ENST00000405623.5	TSL:1	c.133-212A>G		intron	N/A	ENSP00000384092.1
	POMC	ENST00000264708.7	TSL:2	c.133-212A>G		intron	N/A	ENSP00000264708.3

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54505 AN: 151936 Hom.: 11084 Cov.: 32

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.321

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

GnomAD4 genome AF: 0.359 AC: 54561 AN: 152052 Hom.: 11111 Cov.: 32 AF XY: 0.373 AC XY: 27752 AN XY: 74340

African (AFR) AF: 0.506 AC: 21007 AN: 41476

American (AMR) AF: 0.430 AC: 6575 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 737 AN: 3468

East Asian (EAS) AF: 0.597 AC: 3070 AN: 5142

South Asian (SAS) AF: 0.446 AC: 2151 AN: 4818

European-Finnish (FIN) AF: 0.391 AC: 4137 AN: 10580

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.232 AC: 15800 AN: 67966

Other (OTH) AF: 0.321 AC: 677 AN: 2112

Alfa AF: 0.290 Hom.: 12163

Bravo AF: 0.372

Asia WGS AF: 0.511 AC: 1775 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.5
DANN	Benign	0.39
PhyloP100		0.054
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs6713532; hg19: chr2-25384833;