18-13882231-G-C

Variant names:

• chr18-13882231-G-C
• rs1940907
• NM_000529.2:c.*2394C>G

Variant summary

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

The NM_000529.2(MC2R):​c.*2394C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 152,080 control chromosomes in the GnomAD database, including 23,851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23851 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MC2R NM_000529.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.123

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=-1.0).
• BP6: Variant 18-13882231-G-C is Benign according to our data. Variant chr18-13882231-G-C is described in ClinVar as [Benign]. Clinvar id is 326126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC2R	NM_000529.2	c.*2394C>G		3_prime_UTR_variant	Exon 2 of 2	ENST00000327606.4	NP_000520.1
MC2R	NM_001291911.1	c.*2394C>G		3_prime_UTR_variant	Exon 2 of 2		NP_001278840.1
MC2R	XM_017025781.2	c.*2394C>G		3_prime_UTR_variant	Exon 3 of 3		XP_016881270.1
MC2R	XM_047437537.1	c.*2394C>G		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.*2394C>G		3_prime_UTR_variant	Exon 2 of 2	1	NM_000529.2	ENSP00000333821.2

Frequencies

GnomAD3 genomes AF: 0.546 AC: 83038 AN: 151962 Hom.: 23815 Cov.: 33

Gnomad AFR AF: 0.732

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.539

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 AFR exome AF: 0.00

GnomAD4 genome AF: 0.547 AC: 83116 AN: 152080 Hom.: 23851 Cov.: 33 AF XY: 0.546 AC XY: 40609 AN XY: 74368

Gnomad4 AFR AF: 0.733

Gnomad4 AMR AF: 0.492

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.409

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.526

Gnomad4 NFE AF: 0.478

Gnomad4 OTH AF: 0.533

Alfa AF: 0.512 Hom.: 2546

Bravo AF: 0.554

Asia WGS AF: 0.384 AC: 1337 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 12, 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	-1.0
CADD	Benign	0.50
DANN	Benign	0.33

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: rs1940907; hg19: chr18-13882230;