rs4797824

Positions:

• chr18-13884514-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000327606.4(MC2R):​c.*111G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,188,524 control chromosomes in the GnomAD database, including 55,618 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6162 hom., cov: 32)
  • Exomes 𝑓: 0.30 (49456 hom.)
• Consequence: MC2R ENST00000327606.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.741

Genes affected

MC2R (HGNC:6930): (melanocortin 2 receptor) MC2R encodes one member of the five-member G-protein associated melanocortin receptor family. Melanocortins (melanocyte-stimulating hormones and adrenocorticotropic hormone) are peptides derived from pro-opiomelanocortin (POMC). MC2R is selectively activated by adrenocorticotropic hormone, whereas the other four melanocortin receptors recognize a variety of melanocortin ligands. Mutations in MC2R can result in familial glucocorticoid deficiency. Alternate transcript variants have been found for this gene. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 18-13884514-C-T is Benign according to our data. Variant chr18-13884514-C-T is described in ClinVar as [Benign]. Clinvar id is 326188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC2R	NM_000529.2	c.*111G>A		3_prime_UTR_variant	2/2	ENST00000327606.4	NP_000520.1
MC2R	NM_001291911.1	c.*111G>A		3_prime_UTR_variant	2/2		NP_001278840.1
MC2R	XM_017025781.2	c.*111G>A		3_prime_UTR_variant	3/3		XP_016881270.1
MC2R	XM_047437537.1	c.*111G>A		3_prime_UTR_variant	4/4		XP_047293493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MC2R	ENST00000327606.4	c.*111G>A		3_prime_UTR_variant	2/2	1	NM_000529.2	ENSP00000333821	P1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42049 AN: 151916 Hom.: 6166 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.282

GnomAD4 exome AF: 0.304 AC: 314837 AN: 1036490 Hom.: 49456 Cov.: 14 AF XY: 0.300 AC XY: 160135 AN XY: 533564

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.272

Gnomad4 ASJ exome AF: 0.351

Gnomad4 EAS exome AF: 0.246

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.380

Gnomad4 NFE exome AF: 0.321

Gnomad4 OTH exome AF: 0.302

GnomAD4 genome AF: 0.277 AC: 42043 AN: 152034 Hom.: 6162 Cov.: 32 AF XY: 0.277 AC XY: 20574 AN XY: 74294

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.278

Gnomad4 ASJ AF: 0.332

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.369

Gnomad4 NFE AF: 0.324

Gnomad4 OTH AF: 0.277

Alfa AF: 0.316 Hom.: 15144

Bravo AF: 0.268

Asia WGS AF: 0.170 AC: 593 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glucocorticoid deficiency 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.65
DANN	Benign	0.74

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: rs4797824; hg19: chr18-13884513;