NM_000529.2:c.-129+712A>T

Variant names:

• chr18-13914776-T-A
• rs8093607
• NM_000529.2:c.-129+712A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000529.2(MC2R):​c.-129+712A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 152,068 control chromosomes in the GnomAD database, including 12,512 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (12512 hom., cov: 32)
• Consequence: MC2R NM_000529.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.63
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

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.-129+712A>T		intron	N/A	NP_000520.1	Q01718
	MC2R	NM_001291911.1		c.-129+854A>T		intron	N/A	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.-129+712A>T		intron	N/A	ENSP00000333821.2	Q01718
	MC2R	ENST00000946323.1		c.-268+712A>T		intron	N/A	ENSP00000616382.1
	MC2R	ENST00000946324.1		c.-286+712A>T		intron	N/A	ENSP00000616383.1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60080 AN: 151950 Hom.: 12495 Cov.: 32

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.382

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.395 AC: 60131 AN: 152068 Hom.: 12512 Cov.: 32 AF XY: 0.394 AC XY: 29274 AN XY: 74316

African (AFR) AF: 0.523 AC: 21716 AN: 41486

American (AMR) AF: 0.351 AC: 5369 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1291 AN: 3466

East Asian (EAS) AF: 0.191 AC: 988 AN: 5172

South Asian (SAS) AF: 0.198 AC: 955 AN: 4822

European-Finnish (FIN) AF: 0.383 AC: 4051 AN: 10566

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.361 AC: 24539 AN: 67966

Other (OTH) AF: 0.376 AC: 792 AN: 2104

Alfa AF: 0.375 Hom.: 1522

Bravo AF: 0.402

Asia WGS AF: 0.218 AC: 762 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.26
DANN	Benign	0.47
PhyloP100		-1.6
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: rs8093607; hg19: chr18-13914775;