Genetic Variant MC2R:p.Ala126Thr (chr18-13885143-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 7P and 2B. PM1PM2PM5PP2BP4_Moderate

The NM_000529.2(MC2R):c.376G>A(p.Ala126Thr) 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 benign outcome for this variant. 15/22 in silico tools predict a benign 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. A126S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MC2R
NM_000529.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.34

Publications

4 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: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a helix (size 36) in uniprot entity ACTHR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr18-13885143-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 18425.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 familial glucocorticoid deficiency, glucocorticoid deficiency 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.23995686).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC2R	NM_000529.2	MANE Select	c.376G>A	p.Ala126Thr	missense	Exon 2 of 2	NP_000520.1
	MC2R	NM_001291911.1		c.376G>A	p.Ala126Thr	missense	Exon 2 of 2	NP_001278840.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC2R	ENST00000327606.4	TSL:1 MANE Select	c.376G>A	p.Ala126Thr	missense	Exon 2 of 2	ENSP00000333821.2
	MC2R	ENST00000399821.2	TSL:3	c.*6G>A		downstream_gene	N/A	ENSP00000382718.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251336

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0065

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

PhyloP100

2.3

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.76

REVEL

Benign

0.055

Sift

Uncertain

0.027

Sift4G

Uncertain

0.0060

Polyphen

0.032

Vest4

0.097

MutPred

0.61

Loss of stability (P = 0.0453)

MVP

0.44

MPC

0.19

ClinPred

0.22

GERP RS

4.1

Varity_R

0.23

gMVP

0.62

Mutation Taster

=89/11

polymorphism

(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