2-25161300-G-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP7 BS1

The NM_000939.4(POMC):​c.585C>G​(p.Ala195Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,457,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: POMC NM_000939.4 synonymous
• Clinical Significance: Not reported in ClinVar
• 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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP7: Synonymous conserved (PhyloP=-0.088 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000158 (23/1457682) while in subpopulation SAS AF= 0.000234 (20/85518). AF 95% confidence interval is 0.000154. There are 0 homozygotes in gnomad4_exome. There are 18 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POMC	NM_000939.4	c.585C>G	p.Ala195Ala	synonymous_variant	Exon 3 of 3	ENST00000395826.7	NP_000930.1
POMC	NM_001035256.3	c.585C>G	p.Ala195Ala	synonymous_variant	Exon 4 of 4		NP_001030333.1
POMC	NM_001319204.2	c.585C>G	p.Ala195Ala	synonymous_variant	Exon 4 of 4		NP_001306133.1
POMC	NM_001319205.2	c.585C>G	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>G	p.Ala195Ala	synonymous_variant	Exon 3 of 3	2	NM_000939.4	ENSP00000379170.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000338 AC: 8 AN: 236732 Hom.: 0 AF XY: 0.0000619 AC XY: 8 AN XY: 129296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000203

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1457682 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 724910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.0
DANN	Benign	0.41

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;