rs2186944

Variant names:

• chr18-13915543-G-A
• rs2186944
• ENST00000946323.1:c.-323C>T

Variant summary

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

The NM_001291911.1(MC2R):​c.-129+87C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 153,078 control chromosomes in the GnomAD database, including 341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (339 hom., cov: 33)
  • Exomes 𝑓: 0.017 (2 hom.)
• Consequence: MC2R NM_001291911.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.379
• 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=-0.88).
• BP6: Variant 18-13915543-G-A is Benign according to our data. Variant chr18-13915543-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 369250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291911.1. 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_001291911.1		c.-129+87C>T		intron	N/A	NP_001278840.1	Q01718
	MC2R	NM_000529.2	MANE Select	c.-184C>T		upstream_gene	N/A	NP_000520.1	Q01718

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC2R	ENST00000946323.1		c.-323C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000616382.1
	MC2R	ENST00000946325.1		c.-716C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000616384.1
	MC2R	ENST00000946323.1		c.-323C>T		5_prime_UTR	Exon 1 of 3	ENSP00000616382.1

Frequencies

GnomAD3 genomes AF: 0.0445 AC: 6772 AN: 152132 Hom.: 337 Cov.: 33

Gnomad AFR AF: 0.0983

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.0683

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.00575

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00470

Gnomad OTH AF: 0.0373

GnomAD4 exome AF: 0.0169 AC: 14 AN: 828 Hom.: 2 Cov.: 0 AF XY: 0.0106 AC XY: 5 AN XY: 470

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.167 AC: 1 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.0556 AC: 1 AN: 18

East Asian (EAS) AF: 0.263 AC: 10 AN: 38

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 472

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00391 AC: 1 AN: 256

Other (OTH) AF: 0.0294 AC: 1 AN: 34

GnomAD4 genome AF: 0.0446 AC: 6786 AN: 152250 Hom.: 339 Cov.: 33 AF XY: 0.0460 AC XY: 3423 AN XY: 74432

African (AFR) AF: 0.0982 AC: 4079 AN: 41532

American (AMR) AF: 0.0682 AC: 1043 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.180 AC: 936 AN: 5186

South Asian (SAS) AF: 0.0319 AC: 154 AN: 4828

European-Finnish (FIN) AF: 0.00575 AC: 61 AN: 10614

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00470 AC: 320 AN: 68018

Other (OTH) AF: 0.0384 AC: 81 AN: 2112

Alfa AF: 0.0331 Hom.: 37

Bravo AF: 0.0522

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	10
DANN	Benign	0.93
PhyloP100		0.38
PromoterAI		-0.019	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2186944; hg19: chr18-13915542;