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.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC2R	ENST00000327606.4	c.*111G>A		3_prime_UTR_variant	Exon 2 of 2	1	NM_000529.2	ENSP00000333821.2

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glucocorticoid deficiency 1 Benign:1

Jan 13, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs4797824; hg19: chr18-13884513; COSMIC: COSV107388248; COSMIC: COSV107388248;