rs2228479

Positions:

• chr16-89919532-G-A
• chr16-89919532-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:2
• Conservation: PhyloP100: 0.931

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]

ACMG classification

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	UniProt
MC1R	NM_002386.4	c.274G>A	p.Val92Met	missense_variant	1/1	ENST00000555147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555147.2	c.274G>A	p.Val92Met	missense_variant	1/1		NM_002386.4	P1
MC1R	ENST00000555427.1	c.274G>A	p.Val92Met	missense_variant	3/4	5
MC1R	ENST00000639847.1	c.274G>A	p.Val92Met	missense_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.0664 AC: 10102 AN: 152194 Hom.: 550 Cov.: 33

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

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.: 33 AF XY: 0.0852 AC XY: 61888 AN XY: 726518

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.: 33 AF XY: 0.0647 AC XY: 4818 AN XY: 74472

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: 85

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:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

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) -

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	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.0
DANN	Benign	0.83
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.65	T;.;T;T
MetaRNN	Benign	0.0051	T;T;T;T
MetaSVM	Benign	-0.92	T
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	T
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

Other links and lift over

dbSNP: rs2228479; hg19: chr16-89985940; COSMIC: COSV59624495; COSMIC: COSV59624495;