rs104894658

Positions:

chr18-13885298-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP3PP5_Very_StrongBS1_Supporting

The NM_000529.2(MC2R):c.221G>T(p.Ser74Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000458 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 1 hom. )

Consequence

MC2R
NM_000529.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.39

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 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

PP5

Variant 18-13885298-C-A is Pathogenic according to our data. Variant chr18-13885298-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 3258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000475 (695/1461876) while in subpopulation NFE AF= 0.000594 (660/1112000). AF 95% confidence interval is 0.000556. There are 1 homozygotes in gnomad4_exome. There are 348 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MC2R	NM_000529.2 linkuse as main transcript	c.221G>T	p.Ser74Ile	missense_variant	2/2	ENST00000327606.4	NP_000520.1
MC2R	NM_001291911.1 linkuse as main transcript	c.221G>T	p.Ser74Ile	missense_variant	2/2		NP_001278840.1
MC2R	XM_017025781.2 linkuse as main transcript	c.221G>T	p.Ser74Ile	missense_variant	3/3		XP_016881270.1
MC2R	XM_047437537.1 linkuse as main transcript	c.221G>T	p.Ser74Ile	missense_variant	4/4		XP_047293493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MC2R	ENST00000327606.4 linkuse as main transcript	c.221G>T	p.Ser74Ile	missense_variant	2/2	1	NM_000529.2	ENSP00000333821	P1
MC2R	ENST00000399821.2 linkuse as main transcript	c.221G>T	p.Ser74Ile	missense_variant	2/2	3		ENSP00000382718

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000514

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000187

AC:

AN:

251482

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000378

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000475

AC:

695

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000479

AC XY:

348

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000594

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000296

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000514

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000219

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucocorticoid deficiency 1

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Mar 30, 2018	This variant has been previously reported in multiple individuals affected with familial glucocorticoid deficiency (PMID: 8094489, 8069303, 26650942). Additionally, functional characterizations indicate that the p.Ser74Ile variant altered protein function relative to wild type protein (PMID: 12213892 10443676). The p.Ser74 residue is highly conserved, and in silico algorithms predict a damaging effect on protein function. The variant is rare, present as a heterozygous change in the population database gnomAD at a frequency of 0.01% (55/277226), but is not reported as a homozygous change. Based on the combined evidence, the variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 20, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 07, 2023	Variant summary: MC2R c.221G>T (p.Ser74Ile) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of 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 0.00019 in 251482 control chromosomes. This frequency does not allow conclusions about variant significance. c.221G>T has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Glucocorticoid Deficiency, due To ACTH unresponsiveness, a.k.a Familial Glucocorticoid Deficiency (FGD) (example, Weber_1994, Elias_1999, Buonocore_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Elias_1999). The most pronounced variant effect results in an impaired maximal cAMP response due to low affinity for ACTH and no significant signal transducing ability. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 19, 2018	Across a selection of the available literature, the MCR2 c.221G>T (p.Ser74Ile) variant has been identified in upwards of 45 individuals with glucocorticoid deficiency in either a homozygous or compound heterozygous state (Clark and Weber 1994; Lin et al. 2007; Chan et al. 2009; Chung et al. 2010; Matthew et al. 2011; Tsai et al, 2016). The p.Ser74Ile variant is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Functional assays performed by Fluck et al. (2002) and Elias et al. (1999) demonstrated that the p.Ser74Ile variant elicited virtually no measurable enzymatic activity and was associated with an impaired maximal cAMP response when compared to wild type. Based on the collective evidence, the p.Ser74Ile variant is classified as pathogenic for glucocorticoid deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Glucocorticoid Deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Jan 23, 2009

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 02, 2021

This sequence change replaces serine with isoleucine at codon 74 of the MC2R protein (p.Ser74Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is present in population databases (rs104894658, ExAC 0.03%). This missense change has been observed in individuals with FGD and familial glucocorticoid deficiency (FGD) (PMID: 7829641, 12213892, 14960026, 17223989, 19170705, 26650942). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3258). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MC2R function (PMID: 8250922, 9758716, 18840636). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.013

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Pathogenic

3.3

M;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;.

Vest4

0.97

MVP

0.82

MPC

0.82

ClinPred

0.87

GERP RS

4.1

Varity_R

0.98

gMVP

0.83

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