18-13883940-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000529.2(MC2R):c.*685G>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 0.549 in 154,414 control chromosomes in the GnomAD database, including 24,645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.55 (24447 hom., cov: 32)
  • Exomes 𝑓: 0.39 (198 hom.)
• Consequence: MC2R NM_000529.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.647

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 18-13883940-C-T is Benign according to our data. Variant chr18-13883940-C-T is described in ClinVar as [Benign]. Clinvar id is 326174.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC2R	NM_000529.2	c.*685G>A		3_prime_UTR_variant	2/2	ENST00000327606.4
MC2R	NM_001291911.1	c.*685G>A		3_prime_UTR_variant	2/2
MC2R	XM_017025781.2	c.*685G>A		3_prime_UTR_variant	3/3
MC2R	XM_047437537.1	c.*685G>A		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC2R	ENST00000327606.4	c.*685G>A		3_prime_UTR_variant	2/2	1	NM_000529.2	P1

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83858 AN: 151952 Hom.: 24409 Cov.: 32

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.498

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.542

GnomAD4 exome AF: 0.388 AC: 910 AN: 2344 Hom.: 198 Cov.: 0 AF XY: 0.386 AC XY: 468 AN XY: 1212

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.385

Gnomad4 ASJ exome AF: 0.667

Gnomad4 EAS exome AF: 0.346

Gnomad4 SAS exome AF: 0.290

Gnomad4 FIN exome AF: 0.667

Gnomad4 NFE exome AF: 0.400

Gnomad4 OTH exome AF: 0.359

GnomAD4 genome AF: 0.552 AC: 83940 AN: 152070 Hom.: 24447 Cov.: 32 AF XY: 0.551 AC XY: 40965 AN XY: 74328

Gnomad4 AFR AF: 0.751

Gnomad4 AMR AF: 0.494

Gnomad4 ASJ AF: 0.498

Gnomad4 EAS AF: 0.409

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.527

Gnomad4 NFE AF: 0.478

Gnomad4 OTH AF: 0.535

Alfa AF: 0.492 Hom.: 38967

Bravo AF: 0.560

Asia WGS AF: 0.385 AC: 1343 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	5.1
Dann	Benign	0.52

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: rs4308014; hg19: chr18-13883939;