rs104894660

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000529.2(MC2R):c.409C>T(p.Arg137Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

MC2R
NM_000529.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.96

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

PP5

Variant 18-13885110-G-A is Pathogenic according to our data. Variant chr18-13885110-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC2R	NM_000529.2 link	c.409C>T	p.Arg137Trp	missense_variant	Exon 2 of 2	ENST00000327606.4	NP_000520.1	Q01718
MC2R	NM_001291911.1 link	c.409C>T	p.Arg137Trp	missense_variant	Exon 2 of 2		NP_001278840.1	Q01718
MC2R	XM_017025781.2 link	c.409C>T	p.Arg137Trp	missense_variant	Exon 3 of 3		XP_016881270.1	Q01718
MC2R	XM_047437537.1 link	c.409C>T	p.Arg137Trp	missense_variant	Exon 4 of 4		XP_047293493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC2R	ENST00000327606.4 link	c.409C>T	p.Arg137Trp	missense_variant	Exon 2 of 2	1	NM_000529.2	ENSP00000333821.2		Q01718
MC2R	ENST00000399821.2 link	c.*39C>T		downstream_gene_variant		3		ENSP00000382718.2		R4GMM0

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251244

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000279

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucocorticoid deficiency 1

Pathogenic:2

Sep 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 06, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MC2R c.409C>T (p.Arg137Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251244 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MC2R causing Glucocorticoid Deficiency, Due To ACTH Unresponsiveness, allowing no conclusion about variant significance. c.409C>T has been reported in the literature in individuals affected with Glucocorticoid Deficiency (example: Ishii_2000, Fluck_2002, Guran_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence that variant reduced normal activity (Fluck_2002). The following publications have been ascertained in the context of this evaluation (PMID: 12213892, 26523528, 10971458). ClinVar contains an entry for this variant (Variation ID: 3265). Based on the evidence outlined above, the variant was classified as pathogenic. -

Glucocorticoid Deficiency

Pathogenic:1

Apr 16, 2008

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Sep 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.016

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.8

PrimateAI

Benign

0.24

PROVEAN

Pathogenic

-6.8

REVEL

Benign

0.29

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.62

MutPred

0.89

Loss of solvent accessibility (P = 0.1077);

MVP

0.74

MPC

0.43

ClinPred

0.81

GERP RS

2.3

Varity_R

0.74

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over