chr2-25161179-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3B:4O:1

Conservation

PhyloP100: 6.21

Publications

37 publications found

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 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

POMC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 id is 13356.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=3, Likely_benign=1}.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4 link	c.706C>G	p.Arg236Gly	missense_variant	Exon 3 of 3	ENST00000395826.7	NP_000930.1	P01189
POMC	NM_001035256.3 link	c.706C>G	p.Arg236Gly	missense_variant	Exon 4 of 4		NP_001030333.1	P01189
POMC	NM_001319204.2 link	c.706C>G	p.Arg236Gly	missense_variant	Exon 4 of 4		NP_001306133.1	P01189
POMC	NM_001319205.2 link	c.706C>G	p.Arg236Gly	missense_variant	Exon 3 of 3		NP_001306134.1	P01189

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7 link	c.706C>G	p.Arg236Gly	missense_variant	Exon 3 of 3	2	NM_000939.4	ENSP00000379170.2		P01189

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

433

AN:

152214

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00436

AC XY:

3173

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.000627

AC:

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:

AN:

39698

South Asian (SAS)

AF:

0.000104

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

53114

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00531

AC:

5901

AN:

1111986

Other (OTH)

AF:

0.00495

AC:

299

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

434

868

1301

1735

2169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00284

AC:

433

AN:

152332

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

219

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000962

AC:

AN:

41588

American (AMR)

AF:

0.00542

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00384

AC:

261

AN:

68024

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00398

Hom.:

Bravo

AF:

0.00357

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00229

AC:

278

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00534

EpiControl

AF:

0.00445

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1Benign:2

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 29, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in the heterozygous state in multiple individuals with obesity (PMID: 11244459, 12165561, 15951321, 16459314, 18697863, 18091355, 26530524, 28377240); Published functional studies demonstrate a damaging effect (expression of an abnormal fusion protein that interferes with MC4R signaling) (PMID: 12165561); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in control populations; however, the frequency appears to be higher in individuals with obesity, and R236G is felt to confer an increased risk for obesity (PMID: 26530524); This variant is associated with the following publications: (PMID: 22643178, 28377240, 16459314, 16094248, 23028917, 16682835, 12165561, 18697863, 29970488, 17623013, 15951321, 19466204, 18091355, 31650404, 34426522, 35574020, 35562395, 35654930, 36775011, 11244459, 26530524) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

POMC: BS1 -

Obesity due to pro-opiomelanocortin deficiency

Uncertain:1Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 21, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

_x000D_ Criteria applied: PS3_SUP, PS4_SUP, PP1, PP3 -

Obesity due to pro-opiomelanocortin deficiency;C4054476:Inherited obesity

Uncertain:1

Jan 26, 2023

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

POMC-related disorder

Benign:1

Jan 31, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Obesity, early-onset, susceptibility to

Other:1

Aug 15, 2002

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;D;D;D;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.82

T;.;.;.;T

MetaRNN

Benign

0.018

T;T;T;T;T

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.6

M;M;M;M;.

PhyloP100

6.2

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.4

D;D;D;D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;.

Polyphen

1.0

D;D;D;D;.

Vest4

0.98

MVP

0.96

MPC

1.1

ClinPred

0.048

GERP RS

4.2

Varity_R

0.82

gMVP

0.68

Mutation Taster

=11/89

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr2-25161179-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over