rs104894658

Variant names:

• chr18-13885298-C-A
• rs104894658
• NM_000529.2:c.221G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PM1 PP2 PP3 PP5_Very_Strong BS1_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.39

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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a chain Adrenocorticotropic hormone receptor (size 296) in uniprot entity ACTHR_HUMAN there are 24 pathogenic changes around while only 9 benign (73%) in NM_000529.2
• 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 glucocorticoid deficiency 1, familial glucocorticoid deficiency.
• 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. GnomAdExome4 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 GnomAdExome4. There are 348 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC2R	NM_000529.2	c.221G>T	p.Ser74Ile	missense_variant	Exon 2 of 2	ENST00000327606.4	NP_000520.1
MC2R	NM_001291911.1	c.221G>T	p.Ser74Ile	missense_variant	Exon 2 of 2		NP_001278840.1
MC2R	XM_017025781.2	c.221G>T	p.Ser74Ile	missense_variant	Exon 3 of 3		XP_016881270.1
MC2R	XM_047437537.1	c.221G>T	p.Ser74Ile	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	c.221G>T	p.Ser74Ile	missense_variant	Exon 2 of 2	1	NM_000529.2	ENSP00000333821.2
MC2R	ENST00000399821.2	c.221G>T	p.Ser74Ile	missense_variant	Exon 2 of 2	3		ENSP00000382718.2

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152144 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000187 AC: 47 AN: 251482 AF XY: 0.000169

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 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.: 1 Cov.: 32 AF XY: 0.000479 AC XY: 348 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000896 AC: 3 AN: 33478

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53418

Gnomad4 NFE exome AF: 0.000594 AC: 660 AN: 1112000

Gnomad4 Remaining exome AF: 0.000530 AC: 32 AN: 60396

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74320

Gnomad4 AFR AF: 0.000217 AC: 0.000217181 AN: 0.000217181

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000514 AC: 0.000514464 AN: 0.000514464

Gnomad4 OTH AF: 0.000479 AC: 0.000478927 AN: 0.000478927

Alfa AF: 0.000297 Hom.: 0

Bravo AF: 0.000219

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glucocorticoid deficiency 1 Pathogenic:5

Dec 19, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 30, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 20, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 26, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2023

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.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. -

not provided Pathogenic:2

Sep 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MC2R: PM3:Strong, PS3, PM2, PP4:Moderate, BP4 -

Glucocorticoid Deficiency Pathogenic:1

Jan 23, 2009

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Benign	0.40	T
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	D
GERP RS		4.1
Varity_R		0.98
gMVP		0.83
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs104894658; hg19: chr18-13885297;