18-13885137-G-C

Variant names:

• chr18-13885137-G-C
• rs104894657
• NM_000529.2:c.382C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000529.2(MC2R):​c.382C>G​(p.Arg128Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R128C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MC2R NM_000529.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000529.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-13885137-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3261.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 0.0065143 (below the threshold of 3.09). Trascript score misZ: 0.73734 (below the threshold of 3.09). GenCC associations: The gene is linked to glucocorticoid deficiency 1, familial glucocorticoid deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000529.2. 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_000529.2	MANE Select	c.382C>G	p.Arg128Gly	missense	Exon 2 of 2	NP_000520.1	Q01718
	MC2R	NM_001291911.1		c.382C>G	p.Arg128Gly	missense	Exon 2 of 2	NP_001278840.1	Q01718

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC2R	ENST00000327606.4	TSL:1 MANE Select	c.382C>G	p.Arg128Gly	missense	Exon 2 of 2	ENSP00000333821.2	Q01718
	MC2R	ENST00000946323.1		c.382C>G	p.Arg128Gly	missense	Exon 3 of 3	ENSP00000616382.1
	MC2R	ENST00000946324.1		c.382C>G	p.Arg128Gly	missense	Exon 3 of 3	ENSP00000616383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		2.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.79		Gain of sheet (P = 0.1208)
MVP		0.97
MPC		0.86
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.97
Mutation Taster		=19/81	disease causing

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: rs104894657; hg19: chr18-13885136;