chr2-25161223-T-C

Position:

chr2-25161223-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000939.4(POMC):c.662A>G(p.Tyr221Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00166 in 1,613,272 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00090 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 7 hom. )

Consequence

POMC
NM_000939.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.64

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 -9 ACMG points.

BP6

Variant 2-25161223-T-C is Benign according to our data. Variant chr2-25161223-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 898576.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0009 (137/152214) while in subpopulation NFE AF= 0.0016 (109/67998). AF 95% confidence interval is 0.00136. There are 0 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POMC	NM_000939.4 linkuse as main transcript	c.662A>G	p.Tyr221Cys	missense_variant	3/3	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3 linkuse as main transcript	c.662A>G	p.Tyr221Cys	missense_variant	4/4		NP_001030333.1
POMC	NM_001319204.2 linkuse as main transcript	c.662A>G	p.Tyr221Cys	missense_variant	4/4		NP_001306133.1
POMC	NM_001319205.2 linkuse as main transcript	c.662A>G	p.Tyr221Cys	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.662A>G	p.Tyr221Cys	missense_variant	3/3	2	NM_000939.4	ENSP00000379170	P1

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000851

AC:

213

AN:

250296

Hom.:

AF XY:

0.000901

AC XY:

122

AN XY:

135440

show subpopulations

Gnomad AFR exome

AF:

0.000433

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00162

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00173

AC:

2533

AN:

1461058

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

1197

AN XY:

726834

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000403

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00217

Gnomad4 OTH exome

AF:

0.00164

GnomAD4 genome

AF:

0.000900

AC:

137

AN:

152214

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00160

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.000907

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000774

AC:

EpiCase

AF:

0.00153

EpiControl

AF:

0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

POMC-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2024

The POMC c.662A>G variant is predicted to result in the amino acid substitution p.Tyr221Cys. This variant has been reported in the heterozygous state in several individuals with severe early-onset obesity (Lee et al. 2006. PubMed ID: 16459314; Kleinendorst et al. 2018. PubMed ID: 29970488). This variant segregated with obesity among five two-generation families; however, it was also detected in a control subject. Functional analysis in vitro indicated modest changes to protein structure and cell signaling properties (Lee et al. 2006. PubMed ID: 16459314). Another in vitro functional study showed suggestive evidence of loss of function (Table 3 and Supplemental Data Set, Shah et al. 2023. PubMed ID: 36864747). This variant is reported in 0.16% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time its clinical significance remains uncertain due to absence of conclusive genetic and functional evidence. -

Obesity

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2019

Reported previously in published literature, sometimes using alternate nomenclature (Y5C), in association with obesity (Lee et al., 2006; Biebermann et al., 2006; Creemers et al., 2008; Dash et al., 2010; Nordang et al., 2017; Kleinendorst et al., 2018); Seen in multiple family members with obesity from several unrelated families in published literature, but some family members with obesity did not harbor this variant (Lee et al., 2006; Biebermann et al., 2006; Dash et al., 2010); Published functional studies suggest this variant is associated with altered three-dimensional structure of the beta-MSH peptide, reduced binding to MC4R, and decreased generation of cAMP (Lee et al., 2006); This variant is associated with the following publications: (PMID: 16459314, 18091355, 20349035, 18840502, 18697863, 28377240, 29970488, 16459315) -

Obesity due to pro-opiomelanocortin deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;D;D;D;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;.;.;.;D

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.50

D;D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.7

M;M;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-8.3

D;D;D;D;D

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;.

Polyphen

1.0

D;D;D;D;.

Vest4

0.87

MVP

0.97

MPC

1.1

ClinPred

0.13

GERP RS

3.9

Varity_R

0.83

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