rs2236700

Positions:

• chr18-13826392-C-G
• chr18-13826392-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005913.3(MC5R):​c.627C>G​(p.Phe209Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,613,898 control chromosomes in the GnomAD database, including 32,421 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.23 (4230 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28191 hom.)
• Consequence: MC5R NM_005913.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86

Genes affected

MC5R (HGNC:6933): (melanocortin 5 receptor) This gene encodes a member of the seven-pass transmembrane G protein-coupled melanocortin receptor protein family that stimulate cAMP signal transduction. The encoded protein is a receptor for melanocyte-stimulating hormone and adrenocorticotropic hormone and is suggested to play a role in sebum generation. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018680692).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MC5R	NM_005913.3	c.627C>G	p.Phe209Leu	missense_variant	2/2	ENST00000589410.2	NP_005904.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MC5R	ENST00000589410.2	c.627C>G	p.Phe209Leu	missense_variant	2/2	3	NM_005913.3	ENSP00000468086.2
MC5R	ENST00000324750.5	c.627C>G	p.Phe209Leu	missense_variant	1/1	6		ENSP00000318077.3

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34763 AN: 151962 Hom.: 4222 Cov.: 32

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.214

GnomAD3 exomes AF: 0.211 AC: 52947 AN: 251228 Hom.: 6157 AF XY: 0.202 AC XY: 27385 AN XY: 135750

Gnomad AFR exome AF: 0.304

Gnomad AMR exome AF: 0.292

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.350

Gnomad SAS exome AF: 0.143

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.179

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.190 AC: 278089 AN: 1461818 Hom.: 28191 Cov.: 35 AF XY: 0.188 AC XY: 136627 AN XY: 727202

Gnomad4 AFR exome AF: 0.306

Gnomad4 AMR exome AF: 0.293

Gnomad4 ASJ exome AF: 0.176

Gnomad4 EAS exome AF: 0.385

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.172

Gnomad4 NFE exome AF: 0.180

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.229 AC: 34807 AN: 152080 Hom.: 4230 Cov.: 32 AF XY: 0.227 AC XY: 16848 AN XY: 74338

Gnomad4 AFR AF: 0.299

Gnomad4 AMR AF: 0.279

Gnomad4 ASJ AF: 0.176

Gnomad4 EAS AF: 0.363

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.173

Gnomad4 NFE AF: 0.184

Gnomad4 OTH AF: 0.213

Alfa AF: 0.193 Hom.: 2238

Bravo AF: 0.243

TwinsUK AF: 0.175 AC: 650

ALSPAC AF: 0.173 AC: 667

ESP6500AA AF: 0.296 AC: 1304

ESP6500EA AF: 0.179 AC: 1537

ExAC AF: 0.207 AC: 25121

Asia WGS AF: 0.245 AC: 850 AN: 3478

EpiCase AF: 0.185

EpiControl AF: 0.186

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	.;D
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.7	.;D
REVEL	Benign	0.15
Sift	Pathogenic	0.0	.;D
Sift4G	Benign	0.12	.;T
Polyphen		1.0	D;D
Vest4		0.35
MutPred		0.24		Gain of MoRF binding (P = 0.1879);Gain of MoRF binding (P = 0.1879);
MPC		0.94
ClinPred		0.025	T
GERP RS		3.2
Varity_R		0.92

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

LitVar

Other links and lift over

dbSNP: rs2236700; hg19: chr18-13826391; COSMIC: COSV61254381;