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. The variant received -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
• Publications: 13 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 -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 VariationId 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.

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.585C>T	p.Ala195Ala	synonymous	Exon 3 of 3	NP_000930.1	P01189
	POMC	NM_001035256.3		c.585C>T	p.Ala195Ala	synonymous	Exon 4 of 4	NP_001030333.1	P01189
	POMC	NM_001319204.2		c.585C>T	p.Ala195Ala	synonymous	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.585C>T	p.Ala195Ala	synonymous	Exon 3 of 3	ENSP00000379170.2	P01189
	POMC	ENST00000405623.5	TSL:1	c.585C>T	p.Ala195Ala	synonymous	Exon 3 of 3	ENSP00000384092.1	P01189
	POMC	ENST00000264708.7	TSL:2	c.585C>T	p.Ala195Ala	synonymous	Exon 4 of 4	ENSP00000264708.3	P01189

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

GnomAD2 exomes AF: 0.0472 AC: 11174 AN: 236732 AF XY: 0.0459

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 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

African (AFR) AF: 0.00183 AC: 61 AN: 33406

American (AMR) AF: 0.0417 AC: 1840 AN: 44154

Ashkenazi Jewish (ASJ) AF: 0.00771 AC: 200 AN: 25950

East Asian (EAS) AF: 0.299 AC: 11814 AN: 39514

South Asian (SAS) AF: 0.0799 AC: 6834 AN: 85516

European-Finnish (FIN) AF: 0.0435 AC: 2295 AN: 52746

Middle Eastern (MID) AF: 0.00695 AC: 40 AN: 5754

European-Non Finnish (NFE) AF: 0.00207 AC: 2296 AN: 1110430

Other (OTH) AF: 0.0264 AC: 1587 AN: 60182

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

African (AFR) AF: 0.00265 AC: 110 AN: 41580

American (AMR) AF: 0.0274 AC: 419 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.309 AC: 1585 AN: 5136

South Asian (SAS) AF: 0.0977 AC: 471 AN: 4820

European-Finnish (FIN) AF: 0.0434 AC: 461 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00426 AC: 290 AN: 68020

Other (OTH) AF: 0.0284 AC: 60 AN: 2114

Alfa AF: 0.0123 Hom.: 16

Bravo AF: 0.0228

Asia WGS AF: 0.161 AC: 557 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Obesity (1)
-	-	1	Obesity due to pro-opiomelanocortin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.2
DANN	Benign	0.58
PhyloP100		-0.088
Mutation Taster		=100/0	polymorphism (auto)

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