rs2228479

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002386.4(MC1R):c.274G>A(p.Val92Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0851 in 1,612,832 control chromosomes in the GnomAD database, including 7,144 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V92V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.066 ( 554 hom., cov: 33)

Exomes 𝑓: 0.087 ( 6590 hom. )

Consequence

MC1R
NM_002386.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:2

Conservation

PhyloP100: 0.931

Publications

287 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051016808).

BP6

Variant 16-89919532-G-A is Benign according to our data. Variant chr16-89919532-G-A is described in ClinVar as Benign. ClinVar VariationId is 14308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC1R	NM_002386.4 link	c.274G>A	p.Val92Met	missense_variant	Exon 1 of 1	ENST00000555147.2	NP_002377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MC1R	ENST00000555147.2 link	c.274G>A	p.Val92Met	missense_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1
ENSG00000198211	ENST00000556922.1 link	c.274G>A	p.Val92Met	missense_variant	Exon 1 of 5	2		ENSP00000451560.1
MC1R	ENST00000555427.1 link	c.274G>A	p.Val92Met	missense_variant	Exon 3 of 4	5		ENSP00000451760.1
MC1R	ENST00000639847.1 link	c.274G>A	p.Val92Met	missense_variant	Exon 3 of 3	5		ENSP00000492011.1

Frequencies

GnomAD3 genomes

AF:

0.0664

AC:

10102

AN:

152194

Hom.:

550

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0157

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0439

Gnomad ASJ

AF:

0.0631

Gnomad EAS

AF:

0.265

Gnomad SAS

AF:

0.0304

Gnomad FIN

AF:

0.0725

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0895

Gnomad OTH

AF:

0.0627

GnomAD2 exomes

AF:

0.0781

AC:

19399

AN:

248326

AF XY:

0.0762

show subpopulations

Gnomad AFR exome

AF:

0.0161

Gnomad AMR exome

AF:

0.0458

Gnomad ASJ exome

AF:

0.0608

Gnomad EAS exome

AF:

0.276

Gnomad FIN exome

AF:

0.0727

Gnomad NFE exome

AF:

0.0828

Gnomad OTH exome

AF:

0.0667

GnomAD4 exome

AF:

0.0870

AC:

127110

AN:

1460520

Hom.:

6590

Cov.:

AF XY:

0.0852

AC XY:

61888

AN XY:

726518

show subpopulations

African (AFR)

AF:

0.0124

AC:

416

AN:

33478

American (AMR)

AF:

0.0429

AC:

1919

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0595

AC:

1556

AN:

26132

East Asian (EAS)

AF:

0.180

AC:

7161

AN:

39686

South Asian (SAS)

AF:

0.0250

AC:

2155

AN:

86256

European-Finnish (FIN)

AF:

0.0714

AC:

3749

AN:

52500

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0939

AC:

104369

AN:

1111646

Other (OTH)

AF:

0.0943

AC:

5688

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

7637

15275

22912

30550

38187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3904

7808

11712

15616

19520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0664

AC:

10108

AN:

152312

Hom.:

554

Cov.:

AF XY:

0.0647

AC XY:

4818

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0156

AC:

650

AN:

41576

American (AMR)

AF:

0.0438

AC:

670

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0631

AC:

219

AN:

3472

East Asian (EAS)

AF:

0.266

AC:

1373

AN:

5168

South Asian (SAS)

AF:

0.0313

AC:

151

AN:

4832

European-Finnish (FIN)

AF:

0.0725

AC:

770

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0895

AC:

6085

AN:

68014

Other (OTH)

AF:

0.0634

AC:

134

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

485

970

1455

1940

2425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0816

Hom.:

2514

Bravo

AF:

0.0643

TwinsUK

AF:

0.108

AC:

399

ALSPAC

AF:

0.0913

AC:

352

ESP6500AA

AF:

0.0194

AC:

ESP6500EA

AF:

0.0858

AC:

735

ExAC

AF:

0.0759

AC:

9208

Asia WGS

AF:

0.139

AC:

480

AN:

3478

EpiCase

AF:

0.0800

EpiControl

AF:

0.0776

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 5

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 01, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 8990005, 17371441, 28555837, 22464597, 23647022, 24660985, 22854540, 22572819, 24335900, 19924138, 20876876, 24916031, 11487574, 18067130, 16463023, 7581459, 8944016, 12859622, 18366057, 17616515, 9302268, 26103569, 30531825, 31382929, 30414346, 28059796) -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Other:1

Apr 01, 2006

OMIM

Significance:association

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Other:1

Apr 01, 2006

OMIM

Significance:association

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.0

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.10

.;T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.65

T;.;T;T

MetaRNN

Benign

0.0051

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.1

.;L;L;.

PhyloP100

0.93

PROVEAN

Benign

-0.53

N;.;N;N

REVEL

Benign

0.039

Sift

Benign

0.24

T;.;T;D

Sift4G

Benign

0.069

T;.;T;T

Polyphen

0.015

.;B;B;.

Vest4

0.046

MPC

0.018

ClinPred

0.0020

GERP RS

0.17

PromoterAI

0.026

Neutral

(source)

Varity_R

0.071

gMVP

0.27

Mutation Taster

=83/17

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over