rs2228479

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V92L) has been classified as 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 14308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89919532-G-A is described in Lovd as [Likely_benign]. Variant chr16-89919532-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
MC1R	NM_002386.4 linkuse as main transcript	c.274G>A	p.Val92Met	missense_variant	1/1	ENST00000555147.2	NP_002377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MC1R	ENST00000555147.2 linkuse as main transcript	c.274G>A	p.Val92Met	missense_variant	1/1		NM_002386.4	ENSP00000451605	P1
MC1R	ENST00000555427.1 linkuse as main transcript	c.274G>A	p.Val92Met	missense_variant	3/4	5		ENSP00000451760
MC1R	ENST00000639847.1 linkuse as main transcript	c.274G>A	p.Val92Met	missense_variant	3/3	5		ENSP00000492011	P1

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

GnomAD3 exomes

AF:

0.0781

AC:

19399

AN:

248326

Hom.:

1319

AF XY:

0.0762

AC XY:

10284

AN XY:

134878

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 SAS exome

AF:

0.0241

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

Gnomad4 AFR exome

AF:

0.0124

Gnomad4 AMR exome

AF:

0.0429

Gnomad4 ASJ exome

AF:

0.0595

Gnomad4 EAS exome

AF:

0.180

Gnomad4 SAS exome

AF:

0.0250

Gnomad4 FIN exome

AF:

0.0714

Gnomad4 NFE exome

AF:

0.0939

Gnomad4 OTH exome

AF:

0.0943

GnomAD4 genome

AF:

0.0664

AC:

10108

AN:

152312

Hom.:

554

Cov.:

AF XY:

0.0647

AC XY:

4818

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0156

Gnomad4 AMR

AF:

0.0438

Gnomad4 ASJ

AF:

0.0631

Gnomad4 EAS

AF:

0.266

Gnomad4 SAS

AF:

0.0313

Gnomad4 FIN

AF:

0.0725

Gnomad4 NFE

AF:

0.0895

Gnomad4 OTH

AF:

0.0634

Alfa

AF:

0.0829

Hom.:

1063

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2019	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) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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

Other:1

association, no assertion criteria provided

literature only

OMIM

Apr 01, 2006

- -

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

Other:1

association, no assertion criteria provided

literature only

OMIM

Apr 01, 2006

- -

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

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;.

MutationTaster

Benign

0.95

P;P

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

Varity_R

0.071

gMVP

0.27

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