16-89919709-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002386.4(MC1R):c.451C>T(p.Arg151Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0749 in 1,606,188 control chromosomes in the GnomAD database, including 5,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.046 ( 229 hom., cov: 33)

Exomes 𝑓: 0.078 ( 5550 hom. )

Consequence

MC1R
NM_002386.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8O:3

Conservation

PhyloP100: 4.96

Variant links:

Genes affected

MC1R (HGNC:6929): (melanocortin 1 receptor) This intronless gene encodes the receptor protein for melanocyte-stimulating hormone (MSH). The encoded protein, a seven pass transmembrane G protein coupled receptor, controls melanogenesis. Two types of melanin exist: red pheomelanin and black eumelanin. Gene mutations that lead to a loss in function are associated with increased pheomelanin production, which leads to lighter skin and hair color. Eumelanin is photoprotective but pheomelanin may contribute to UV-induced skin damage by generating free radicals upon UV radiation. Binding of MSH to its receptor activates the receptor and stimulates eumelanin synthesis. This receptor is a major determining factor in sun sensitivity and is a genetic risk factor for melanoma and non-melanoma skin cancer. Over 30 variant alleles have been identified which correlate with skin and hair color, providing evidence that this gene is an important component in determining normal human pigment variation. [provided by RefSeq, Jul 2008]

MC1R links:

ENSG00000198211 (HGNC:):

ENSG00000198211 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007609129).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC1R	NM_002386.4 link	c.451C>T	p.Arg151Cys	missense_variant	Exon 1 of 1	ENST00000555147.2	NP_002377.4	Q01726Q1JUL4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555147.2 link	c.451C>T	p.Arg151Cys	missense_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1		Q01726
ENSG00000198211	ENST00000556922.1 link	c.451C>T	p.Arg151Cys	missense_variant	Exon 1 of 5	2		ENSP00000451560.1		A0A0B4J269

Frequencies

GnomAD3 genomes

AF:

0.0463

AC:

7044

AN:

152234

Hom.:

229

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0148

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.0167

Gnomad ASJ

AF:

0.0746

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.0699

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0741

Gnomad OTH

AF:

0.0272

GnomAD3 exomes

AF:

0.0442

AC:

10719

AN:

242744

Hom.:

427

AF XY:

0.0447

AC XY:

5902

AN XY:

132162

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.00937

Gnomad ASJ exome

AF:

0.0656

Gnomad EAS exome

AF:

0.000613

Gnomad SAS exome

AF:

0.00363

Gnomad FIN exome

AF:

0.0705

Gnomad NFE exome

AF:

0.0718

Gnomad OTH exome

AF:

0.0412

GnomAD4 exome

AF:

0.0779

AC:

113202

AN:

1453836

Hom.:

5550

Cov.:

AF XY:

0.0754

AC XY:

54534

AN XY:

723648

show subpopulations

Gnomad4 AFR exome

AF:

0.0111

Gnomad4 AMR exome

AF:

0.0112

Gnomad4 ASJ exome

AF:

0.0677

Gnomad4 EAS exome

AF:

0.000705

Gnomad4 SAS exome

AF:

0.00400

Gnomad4 FIN exome

AF:

0.0665

Gnomad4 NFE exome

AF:

0.0928

Gnomad4 OTH exome

AF:

0.0643

GnomAD4 genome

AF:

0.0462

AC:

7045

AN:

152352

Hom.:

229

Cov.:

AF XY:

0.0444

AC XY:

3304

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0148

Gnomad4 AMR

AF:

0.0167

Gnomad4 ASJ

AF:

0.0746

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.00476

Gnomad4 FIN

AF:

0.0699

Gnomad4 NFE

AF:

0.0741

Gnomad4 OTH

AF:

0.0270

Alfa

AF:

0.0658

Hom.:

302

Bravo

AF:

0.0434

TwinsUK

AF:

0.0995

AC:

369

ALSPAC

AF:

0.0900

AC:

347

ESP6500AA

AF:

0.0171

AC:

ESP6500EA

AF:

0.0762

AC:

655

ExAC

AF:

0.0446

AC:

5409

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8Other:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Jul 21, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_supporting, PS4_moderate -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MC1R p.(Arg151Cys) variant was not identified in the Cosmic or MutDB databases however it was identified in dbSNP (ID: rs1805007) as we all as ClinVar (reported as benign by Prevention Genetics and by Invitae for Cutaneous malignant melanoma 5, reported as pathogenic by GeneDx and reported as likely benign by Illumina for Malignant Melanoma Susceptibility), Clinvitae and LOVD 3.0. The variant was identified in control databases in 12284 of 274116 chromosomes (466 homozygous) at a frequency of 0.044813 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 9141 of 127252 chromosomes (freq: 0.07183), European (Finnish) in 1376 of 19504 chromosomes (freq: 0.07055), Ashkenazi Jewish in 670 of 10300 chromosomes (freq: 0.06505), other in 302 of 7104 chromosomes (freq: 0.04251), African in 333 of 24564 chromosomes (freq: 0.01356), Latino in 338 of 35330 chromosomes (freq: 0.009567), South Asian in 111 of 30564 chromosomes (freq: 0.003632) and East Asian in 13 of 19498 chromosomes (freq: 0.000667). This variant has been found through genome wide association studies to be associated with an increased risk of skin cancer (Tagliabue_2015_26103569). The p.Arg151 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the R variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. References: Tagliabue, Elena, et al. "MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project." British journal of cancer 113.2 (2015): 354. -

Jan 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a dominant negative effect on expression, which results in a decrease in the receptor's ability to elevate intracellular cAMP levels and a complete loss of receptor function at the cell surface (Beaumont et al., 2007; Sanchez-Laorden et al., 2009); This variant is associated with the following publications: (PMID: 23392294, 19799798, 19452503, 19924138, 10403794, 24665948, 23522749, 19269164, 24660985, 11875032, 24081230, 18366057, 22572819, 20876876, 19656326, 17616515, 9571181, 9302268, 11179997, 26103569, 27251790, 23647022, 24335900, 30531825, 31382929, 30414346, 14709592, 27924526, 11500805, 11500806) -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Melanoma, cutaneous malignant, susceptibility to, 5

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Skin/hair/eye pigmentation 2, red hair/fair skin

Other:1

May 01, 2015

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Increased analgesia from kappa-opioid receptor agonist, female-specific

Other:1

May 01, 2015

OMIM

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: literature only

- -

ALBINISM, OCULOCUTANEOUS, TYPE II, MODIFIER OF

Other:1

May 01, 2015

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

.;D;D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

T;.;T;T

MetaRNN

Benign

0.0076

T;T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.5

.;M;M;.

PROVEAN

Pathogenic

-7.4

D;.;D;N

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Uncertain

0.013

D;.;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.72

MPC

0.13

ClinPred

0.090

GERP RS

4.8

Varity_R

0.76

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over