rs28932472

Variant names:

• chr2-25161179-G-C
• rs28932472
• NM_000939.4:c.706C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-25161179-G-C
• chr2-25161179-G-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_000939.4(POMC):​c.706C>G​(p.Arg236Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00434 in 1,613,852 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (28 hom.)
• Consequence: POMC NM_000939.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3 B:4 O:1
• Conservation: PhyloP100: 6.21
• Publications: 37 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• inherited obesity

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.017676592).
• BP6: Variant 2-25161179-G-C is Benign according to our data. Variant chr2-25161179-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13356.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00284 (433/152332) while in subpopulation AMR AF = 0.00542 (83/15304). AF 95% confidence interval is 0.00448. There are 1 homozygotes in GnomAd4. There are 219 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 28 AR,SD,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	NM_000939.4	MANE Select	c.706C>G	p.Arg236Gly	missense	Exon 3 of 3	NP_000930.1	P01189
	POMC	NM_001035256.3		c.706C>G	p.Arg236Gly	missense	Exon 4 of 4	NP_001030333.1	P01189
	POMC	NM_001319204.2		c.706C>G	p.Arg236Gly	missense	Exon 4 of 4	NP_001306133.1	P01189

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POMC	ENST00000395826.7	TSL:2 MANE Select	c.706C>G	p.Arg236Gly	missense	Exon 3 of 3	ENSP00000379170.2	P01189
	POMC	ENST00000405623.5	TSL:1	c.706C>G	p.Arg236Gly	missense	Exon 3 of 3	ENSP00000384092.1	P01189
	POMC	ENST00000264708.7	TSL:2	c.706C>G	p.Arg236Gly	missense	Exon 4 of 4	ENSP00000264708.3	P01189

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 433 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00269 AC: 675 AN: 250890 AF XY: 0.00259

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00775

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.00396

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00449 AC: 6569 AN: 1461520 Hom.: 28 Cov.: 32 AF XY: 0.00436 AC XY: 3173 AN XY: 727076

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00322 AC: 144 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00704 AC: 184 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86248

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53114

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00531 AC: 5901 AN: 1111986

Other (OTH) AF: 0.00495 AC: 299 AN: 60386

GnomAD4 genome AF: 0.00284 AC: 433 AN: 152332 Hom.: 1 Cov.: 33 AF XY: 0.00294 AC XY: 219 AN XY: 74494

African (AFR) AF: 0.000962 AC: 40 AN: 41588

American (AMR) AF: 0.00542 AC: 83 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00384 AC: 261 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00398 Hom.: 0

Bravo AF: 0.00357

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00229 AC: 278

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00445

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	2	not provided (6)
-	1	1	Obesity due to pro-opiomelanocortin deficiency (2)
-	1	-	Obesity due to pro-opiomelanocortin deficiency;C4054476:Inherited obesity (1)
-	-	1	POMC-related disorder (1)
-	-	-	Obesity, early-onset, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.96
MPC		1.1
ClinPred		0.048	T
GERP RS		4.2
Varity_R		0.82
gMVP		0.68
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs28932472; hg19: chr2-25384048; COSMIC: COSV99063086; COSMIC: COSV99063086;