Genetic Variant NM_000529.2:c.221G>T (chr18-13885298-C-A) – ACMG Classification: Pathogenic (15 pts)

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PS3PM1PP2PP3PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000914807: 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." and additional evidence is available in ClinVar.

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:9

Conservation

PhyloP100: 7.39

Publications

33 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000914807: 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.; SCV000996121: "functional characterizations indicate that the p.Ser74Ile variant altered protein function relative to wild type protein." PMID:12213892 10443676; SCV003800803: The most pronounced variant effect results in an impaired maximal cAMP response due to low affinity for ACTH and no significant signal transducing ability. Elias_1999; SCV003285382: Experimental studies have shown that this missense change affects MC2R function (PMID: 8250922, 9758716, 18840636).

PM1

In a disulfide_bond (size 232) in uniprot entity ACTHR_HUMAN there are 17 pathogenic changes around while only 3 benign (85%) 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 VariationId 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 passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.221G>T	p.Ser74Ile	missense	Exon 2 of 2	NP_000520.1	Q01718
	MC2R	NM_001291911.1		c.221G>T	p.Ser74Ile	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.221G>T	p.Ser74Ile	missense	Exon 2 of 2	ENSP00000333821.2	Q01718
MC2R	ENST00000946323.1		c.221G>T	p.Ser74Ile	missense	Exon 3 of 3	ENSP00000616382.1
MC2R	ENST00000946324.1		c.221G>T	p.Ser74Ile	missense	Exon 3 of 3	ENSP00000616383.1

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

GnomAD2 exomes

AF:

0.000187

AC:

AN:

251482

AF XY:

0.000169

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 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

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000594

AC:

660

AN:

1112000

Other (OTH)

AF:

0.000530

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000296

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000514

AC:

AN:

68032

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000297

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

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glucocorticoid deficiency 1 (6)

not provided (2)

Glucocorticoid Deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.82

M_CAP

Benign

0.013

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

-0.11

MutationAssessor

Pathogenic

3.3

PhyloP100

7.4

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.97

MVP

0.82

MPC

0.82

ClinPred

0.87

GERP RS

4.1

Varity_R

0.98

gMVP

0.83

Mutation Taster

=8/92

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over