rs28940892

Variant names:

• chr18-13884758-T-A
• NM_000529.2:c.761A>T

Your query was ambiguous. Multiple possible variants found:

• chr18-13884758-T-A
• chr18-13884758-T-C
• chr18-13884758-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000529.2(MC2R):​c.761A>T​(p.Tyr254Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MC2R NM_000529.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.56

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC2R	NM_000529.2	c.761A>T	p.Tyr254Phe	missense_variant	Exon 2 of 2	ENST00000327606.4	NP_000520.1
MC2R	NM_001291911.1	c.761A>T	p.Tyr254Phe	missense_variant	Exon 2 of 2		NP_001278840.1
MC2R	XM_017025781.2	c.761A>T	p.Tyr254Phe	missense_variant	Exon 3 of 3		XP_016881270.1
MC2R	XM_047437537.1	c.761A>T	p.Tyr254Phe	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.761A>T	p.Tyr254Phe	missense_variant	Exon 2 of 2	1	NM_000529.2	ENSP00000333821.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461828 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0038	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.22
Sift	Benign	0.80	T
Sift4G	Benign	0.53	T
Polyphen		1.0	D
Vest4		0.29
MutPred		0.71		Loss of catalytic residue at Y254 (P = 0.0862);
MVP		0.57
MPC		0.72
ClinPred		0.90	D
GERP RS		5.1
Varity_R		0.45
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-13884757;