rs28926182

chr18-13884686-A-Cchr18-13884686-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000529.2(MC2R):c.833T>G(p.Phe278Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,614,126 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (113 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (135 hom.)
• Consequence: MC2R NM_000529.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 8.70

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 -18 ACMG points.

• PM1: In a chain Adrenocorticotropic hormone receptor (size 296) in uniprot entity ACTHR_HUMAN there are 23 pathogenic changes around while only 9 benign (72%) in NM_000529.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.011311591).
• BP6: Variant 18-13884686-A-C is Benign according to our data. Variant chr18-13884686-A-C is described in ClinVar as [Benign]. Clinvar id is 326191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-13884686-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC2R	NM_000529.2	c.833T>G	p.Phe278Cys	missense_variant	2/2	ENST00000327606.4
MC2R	NM_001291911.1	c.833T>G	p.Phe278Cys	missense_variant	2/2
MC2R	XM_017025781.2	c.833T>G	p.Phe278Cys	missense_variant	3/3
MC2R	XM_047437537.1	c.833T>G	p.Phe278Cys	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC2R	ENST00000327606.4	c.833T>G	p.Phe278Cys	missense_variant	2/2	1	NM_000529.2	P1

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3333 AN: 152168 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.0755

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00583 AC: 1465 AN: 251382 Hom.: 60 AF XY: 0.00423 AC XY: 574 AN XY: 135854

Gnomad AFR exome AF: 0.0809

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00239 AC: 3499 AN: 1461840 Hom.: 135 Cov.: 32 AF XY: 0.00203 AC XY: 1478 AN XY: 727212

Gnomad4 AFR exome AF: 0.0840

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.00452

GnomAD4 genome AF: 0.0220 AC: 3344 AN: 152286 Hom.: 113 Cov.: 32 AF XY: 0.0214 AC XY: 1591 AN XY: 74468

Gnomad4 AFR AF: 0.0755

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00364 Hom.: 41

Bravo AF: 0.0249

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0733 AC: 323

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00709 AC: 861

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Glucocorticoid deficiency 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

MC2R-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.77
MPC		0.81
ClinPred		0.032	T
GERP RS		5.1
Varity_R		0.70
gMVP		0.81

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: rs28926182; hg19: chr18-13884685;