rs267607231

chr18-13885143-C-Achr18-13885143-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_000529.2(MC2R):c.376G>T(p.Ala126Ser) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A126V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MC2R NM_000529.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.34

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 Likely_pathogenic. Variant got 6 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831
• PP5: Variant 18-13885143-C-A is Pathogenic according to our data. Variant chr18-13885143-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 18425.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC2R	NM_000529.2	c.376G>T	p.Ala126Ser	missense_variant	2/2	ENST00000327606.4
MC2R	NM_001291911.1	c.376G>T	p.Ala126Ser	missense_variant	2/2
MC2R	XM_017025781.2	c.376G>T	p.Ala126Ser	missense_variant	3/3
MC2R	XM_047437537.1	c.376G>T	p.Ala126Ser	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC2R	ENST00000327606.4	c.376G>T	p.Ala126Ser	missense_variant	2/2	1	NM_000529.2	P1
MC2R	ENST00000399821.2			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Glucocorticoid deficiency 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0065	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.27	B
Vest4		0.72
MutPred		0.85		Loss of stability (P = 0.0435);
MVP		0.46
MPC		0.25
ClinPred		0.79	D
GERP RS		4.1
Varity_R		0.59
gMVP		0.65

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: rs267607231; hg19: chr18-13885142;