Genetic Variant MC2R:p.Tyr254Cys (chr18-13884758-T-C) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_000529.2(MC2R):c.761A>G(p.Tyr254Cys) 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).

Frequency

Genomes: not found (cov: 32)

Consequence

MC2R
NM_000529.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.56

Publications

16 publications found

Variant links:

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

MC2R links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a chain Adrenocorticotropic hormone receptor (size 296) in uniprot entity ACTHR_HUMAN there are 20 pathogenic changes around while only 7 benign (74%) in NM_000529.2

PM2

Very rare variant in population databases, with high coverage;

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 familial glucocorticoid deficiency, glucocorticoid deficiency 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 18-13884758-T-C is Pathogenic according to our data. Variant chr18-13884758-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3266.Status of the report is no_assertion_criteria_provided, 0 stars.

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.761A>G	p.Tyr254Cys	missense	Exon 2 of 2	NP_000520.1	Q01718
	MC2R	NM_001291911.1		c.761A>G	p.Tyr254Cys	missense	Exon 2 of 2	NP_001278840.1	Q01718

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MC2R	ENST00000327606.4	TSL:1 MANE Select	c.761A>G	p.Tyr254Cys	missense	Exon 2 of 2	ENSP00000333821.2	Q01718
MC2R	ENST00000946323.1		c.761A>G	p.Tyr254Cys	missense	Exon 3 of 3	ENSP00000616382.1
MC2R	ENST00000946324.1		c.761A>G	p.Tyr254Cys	missense	Exon 3 of 3	ENSP00000616383.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000295

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glucocorticoid deficiency 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.012

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.9

PhyloP100

3.6

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.84

MutPred

0.86

Gain of helix (P = 0.132)

MVP

0.83

MPC

0.85

ClinPred

1.0

GERP RS

5.1

Varity_R

0.92

gMVP

0.90

Mutation Taster

=18/82

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over