rs2071345

Variant names:

• chr2-25161300-G-A
• rs2071345
• NM_000939.4:c.585C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-25161300-G-A
• chr2-25161300-G-C
• chr2-25161300-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000939.4(POMC):​c.585C>T​(p.Ala195Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,609,920 control chromosomes in the GnomAD database, including 2,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (305 hom., cov: 33)
  • Exomes 𝑓: 0.019 (2315 hom.)
• Consequence: POMC NM_000939.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0880

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-25161300-G-A is Benign according to our data. Variant chr2-25161300-G-A is described in ClinVar as [Benign]. Clinvar id is 335354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.088 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4	c.585C>T	p.Ala195Ala	synonymous_variant	Exon 3 of 3	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.585C>T	p.Ala195Ala	synonymous_variant	Exon 4 of 4		NP_001030333.1
POMC	NM_001319204.2	c.585C>T	p.Ala195Ala	synonymous_variant	Exon 4 of 4		NP_001306133.1
POMC	NM_001319205.2	c.585C>T	p.Ala195Ala	synonymous_variant	Exon 3 of 3		NP_001306134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POMC	ENST00000395826.7	c.585C>T	p.Ala195Ala	synonymous_variant	Exon 3 of 3	2	NM_000939.4	ENSP00000379170.2

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3419 AN: 152150 Hom.: 305 Cov.: 33

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0274

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.0970

Gnomad FIN AF: 0.0434

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0472 AC: 11174 AN: 236732 Hom.: 1098 AF XY: 0.0459 AC XY: 5937 AN XY: 129296

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.0440

Gnomad ASJ exome AF: 0.00782

Gnomad EAS exome AF: 0.325

Gnomad SAS exome AF: 0.0827

Gnomad FIN exome AF: 0.0444

Gnomad NFE exome AF: 0.00369

Gnomad OTH exome AF: 0.0239

GnomAD4 exome AF: 0.0185 AC: 26967 AN: 1457652 Hom.: 2315 Cov.: 32 AF XY: 0.0200 AC XY: 14475 AN XY: 724902

Gnomad4 AFR exome AF: 0.00183

Gnomad4 AMR exome AF: 0.0417

Gnomad4 ASJ exome AF: 0.00771

Gnomad4 EAS exome AF: 0.299

Gnomad4 SAS exome AF: 0.0799

Gnomad4 FIN exome AF: 0.0435

Gnomad4 NFE exome AF: 0.00207

Gnomad4 OTH exome AF: 0.0264

GnomAD4 genome AF: 0.0224 AC: 3413 AN: 152268 Hom.: 305 Cov.: 33 AF XY: 0.0273 AC XY: 2033 AN XY: 74436

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.0274

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.309

Gnomad4 SAS AF: 0.0977

Gnomad4 FIN AF: 0.0434

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0123 Hom.: 16

Bravo AF: 0.0228

Asia WGS AF: 0.161 AC: 557 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Obesity Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Obesity due to pro-opiomelanocortin deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.2
DANN	Benign	0.58

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

Other links and lift over

dbSNP: rs2071345; hg19: chr2-25384169; COSMIC: COSV53034951; COSMIC: COSV53034951;