rs4797824

Variant names:

• chr18-13884514-C-T
• rs4797824
• NM_000529.2:c.*111G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000529.2(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 NM_000529.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.741
• Publications: 10 publications found

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]

MC2R Gene-Disease associations (from GenCC):

• glucocorticoid deficiency 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• familial glucocorticoid deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000529.2. 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
	MC2R	NM_000529.2	MANE Select	c.*111G>A		3_prime_UTR	Exon 2 of 2	NP_000520.1	Q01718
	MC2R	NM_001291911.1		c.*111G>A		3_prime_UTR	Exon 2 of 2	NP_001278840.1	Q01718

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC2R	ENST00000327606.4	TSL:1 MANE Select	c.*111G>A		3_prime_UTR	Exon 2 of 2	ENSP00000333821.2	Q01718
	MC2R	ENST00000946323.1		c.*111G>A		3_prime_UTR	Exon 3 of 3	ENSP00000616382.1
	MC2R	ENST00000946324.1		c.*111G>A		3_prime_UTR	Exon 3 of 3	ENSP00000616383.1

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

African (AFR) AF: 0.192 AC: 4896 AN: 25492

American (AMR) AF: 0.272 AC: 11689 AN: 43032

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 8268 AN: 23542

East Asian (EAS) AF: 0.246 AC: 9284 AN: 37756

South Asian (SAS) AF: 0.167 AC: 12760 AN: 76406

European-Finnish (FIN) AF: 0.380 AC: 14724 AN: 38784

Middle Eastern (MID) AF: 0.336 AC: 1143 AN: 3402

European-Non Finnish (NFE) AF: 0.321 AC: 237949 AN: 741238

Other (OTH) AF: 0.302 AC: 14124 AN: 46838

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

African (AFR) AF: 0.195 AC: 8089 AN: 41474

American (AMR) AF: 0.278 AC: 4254 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1150 AN: 3466

East Asian (EAS) AF: 0.192 AC: 993 AN: 5160

South Asian (SAS) AF: 0.157 AC: 756 AN: 4816

European-Finnish (FIN) AF: 0.369 AC: 3892 AN: 10558

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 22009 AN: 67956

Other (OTH) AF: 0.277 AC: 586 AN: 2114

Alfa AF: 0.311 Hom.: 19737

Bravo AF: 0.268

Asia WGS AF: 0.170 AC: 593 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Glucocorticoid deficiency 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.65
DANN	Benign	0.74
PhyloP100		-0.74
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4797824;

hg19: chr18-13884513;

COSMIC: COSV107388248;

COSMIC: COSV107388248;