rs79533878

Variant names:

• chr18-13915538-A-G
• rs79533878
• NM_001291911.1:c.-129+92T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001291911.1(MC2R):​c.-129+92T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0849 in 153,106 control chromosomes in the GnomAD database, including 720 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (713 hom., cov: 33)
  • Exomes 𝑓: 0.11 (7 hom.)
• Consequence: MC2R NM_001291911.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.520
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 18-13915538-A-G is Benign according to our data. Variant chr18-13915538-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 369249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291911.1. 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_001291911.1		c.-129+92T>C		intron	N/A	NP_001278840.1
	MC2R	NM_000529.2	MANE Select	c.-179T>C		upstream_gene	N/A	NP_000520.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC2R	ENST00000399821.2	TSL:3	c.-129+92T>C		intron	N/A	ENSP00000382718.2
	MC2R	ENST00000327606.4	TSL:1 MANE Select	c.-179T>C		upstream_gene	N/A	ENSP00000333821.2

Frequencies

GnomAD3 genomes AF: 0.0849 AC: 12920 AN: 152156 Hom.: 714 Cov.: 33

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0810

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.0637

Gnomad FIN AF: 0.0901

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0755

GnomAD4 exome AF: 0.106 AC: 88 AN: 832 Hom.: 7 Cov.: 0 AF XY: 0.119 AC XY: 57 AN XY: 478

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.0556 AC: 1 AN: 18

East Asian (EAS) AF: 0.310 AC: 13 AN: 42

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.0949 AC: 45 AN: 474

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0923 AC: 24 AN: 260

Other (OTH) AF: 0.143 AC: 4 AN: 28

GnomAD4 genome AF: 0.0848 AC: 12915 AN: 152274 Hom.: 713 Cov.: 33 AF XY: 0.0851 AC XY: 6335 AN XY: 74462

African (AFR) AF: 0.0317 AC: 1317 AN: 41572

American (AMR) AF: 0.120 AC: 1834 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0810 AC: 281 AN: 3470

East Asian (EAS) AF: 0.187 AC: 967 AN: 5176

South Asian (SAS) AF: 0.0636 AC: 307 AN: 4830

European-Finnish (FIN) AF: 0.0901 AC: 955 AN: 10604

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 6985 AN: 68008

Other (OTH) AF: 0.0738 AC: 156 AN: 2114

Alfa AF: 0.0664 Hom.: 109

Bravo AF: 0.0876

Asia WGS AF: 0.125 AC: 435 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Glucocorticoid Deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.29
PhyloP100		-0.52
PromoterAI		-0.024	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs79533878; hg19: chr18-13915537; COSMIC: COSV59619170; COSMIC: COSV59619170;