rs193046675

Variant names:

• chr18-13882560-C-T
• rs193046675
• NM_000529.2:c.*2065G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000529.2(MC2R):​c.*2065G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000683 in 152,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MC2R NM_000529.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.299
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 18-13882560-C-T is Benign according to our data. Variant chr18-13882560-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 891402.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000683 (104/152260) while in subpopulation SAS AF = 0.00559 (27/4826). AF 95% confidence interval is 0.00395. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.*2065G>A		3_prime_UTR	Exon 2 of 2	NP_000520.1	Q01718
	MC2R	NM_001291911.1		c.*2065G>A		3_prime_UTR	Exon 2 of 2	NP_001278840.1	Q01718

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC2R	ENST00000327606.4	TSL:1 MANE Select	c.*2065G>A		3_prime_UTR	Exon 2 of 2	ENSP00000333821.2	Q01718
	MC2R	ENST00000946323.1		c.*2065G>A		3_prime_UTR	Exon 3 of 3	ENSP00000616382.1
	MC2R	ENST00000946324.1		c.*2065G>A		downstream_gene	N/A	ENSP00000616383.1

Frequencies

GnomAD3 genomes AF: 0.000684 AC: 104 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000478

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74446

African (AFR) AF: 0.0000722 AC: 3 AN: 41544

American (AMR) AF: 0.000392 AC: 6 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4826

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000476 Hom.: 0

Bravo AF: 0.000389

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Glucocorticoid deficiency 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.66
PhyloP100		0.30

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: rs193046675; hg19: chr18-13882559;