2-25161179-G-C

Position:

chr2-25161179-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3BP4_StrongBS1BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R236Q) has been classified as Likely benign.

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:3O:1

Conservation

PhyloP100: 6.21

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 Benign. Variant got -11 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Eigen, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.017676592).

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 28 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POMC	NM_000939.4 linkuse as main transcript	c.706C>G	p.Arg236Gly	missense_variant	3/3	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3 linkuse as main transcript	c.706C>G	p.Arg236Gly	missense_variant	4/4		NP_001030333.1
POMC	NM_001319204.2 linkuse as main transcript	c.706C>G	p.Arg236Gly	missense_variant	4/4		NP_001306133.1
POMC	NM_001319205.2 linkuse as main transcript	c.706C>G	p.Arg236Gly	missense_variant	3/3		NP_001306134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7 linkuse as main transcript	c.706C>G	p.Arg236Gly	missense_variant	3/3	2	NM_000939.4	ENSP00000379170	P1

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

GnomAD3 exomes

AF:

0.00269

AC:

675

AN:

250890

Hom.:

AF XY:

0.00259

AC XY:

352

AN XY:

135696

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 SAS exome

AF:

0.0000327

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

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00322

Gnomad4 ASJ exome

AF:

0.00704

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.000188

Gnomad4 NFE exome

AF:

0.00531

Gnomad4 OTH exome

AF:

0.00495

GnomAD4 genome

AF:

0.00284

AC:

433

AN:

152332

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

219

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000962

Gnomad4 AMR

AF:

0.00542

Gnomad4 ASJ

AF:

0.00865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00384

Gnomad4 OTH

AF:

0.00378

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:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1Benign:1

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	The R236G variant in the POMC gene has been reported previously in the heterozygous state in multiple individuals with obesity (Miraglia del Giudice et al., 2001; Challis et al., 2002; Buono et al., 2005; Lee et al., 2006; Creemers et al., 2008; Dubern et al., 2008; Shabana et al., 2016; Nordang et al., 2017). While it has also been reported in control populations, the frequency appears to be higher in individuals with obesity, and R236G is felt to confer an increased risk for obesity (Shabana et al., 2016). The R236G variant is observed in 234/66,206 (0.35%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The R236G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution disrupts the dibasic cleavage site at a position that is conserved across species (Challis et al., 2002). Functional studies demonstrate that R236G is associated with expression of an abnormal fusion protein that interferes with MC4R signaling (Challis et al., 2002). We interpret R236G as a risk allele. -

Obesity due to pro-opiomelanocortin deficiency

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 21, 2022	_x000D_ Criteria applied: PS3_SUP, PS4_SUP, PP1, PP3 -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jan 26, 2023

- -

POMC-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

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

risk factor, no assertion criteria provided

literature only

OMIM

Aug 15, 2002

- -

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

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;.

MutationTaster

Benign

1.0

D;D;D;D

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

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

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