rs1805006

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5BP4_StrongBP6BS2

The NM_002386.4(MC1R):c.252C>A(p.Asp84Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00948 in 1,613,160 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D84?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0053 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0099 ( 98 hom. )

Consequence

MC1R
NM_002386.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6O:1

Conservation

PhyloP100: 5.00

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 -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-89919510-C-R is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.014244467).

BP6

Variant 16-89919510-C-A is Benign according to our data. Variant chr16-89919510-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14309.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Uncertain_significance=1}. Variant chr16-89919510-C-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 811 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC1R	NM_002386.4 link	c.252C>A	p.Asp84Glu	missense_variant	Exon 1 of 1	ENST00000555147.2	NP_002377.4	Q01726Q1JUL4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MC1R	ENST00000555147.2 link	c.252C>A	p.Asp84Glu	missense_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1	Q01726
ENSG00000198211	ENST00000556922.1 link	c.252C>A	p.Asp84Glu	missense_variant	Exon 1 of 5	2		ENSP00000451560.1	A0A0B4J269
MC1R	ENST00000555427.1 link	c.252C>A	p.Asp84Glu	missense_variant	Exon 3 of 4	5		ENSP00000451760.1	G3V4F0
MC1R	ENST00000639847.1 link	c.252C>A	p.Asp84Glu	missense_variant	Exon 3 of 3	5		ENSP00000492011.1	Q01726

Frequencies

GnomAD3 genomes

AF:

0.00533

AC:

811

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00980

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00524

AC:

1304

AN:

248704

Hom.:

AF XY:

0.00518

AC XY:

699

AN XY:

135010

show subpopulations

Gnomad AFR exome

AF:

0.00167

Gnomad AMR exome

AF:

0.00206

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00177

Gnomad NFE exome

AF:

0.00989

Gnomad OTH exome

AF:

0.00595

GnomAD4 exome

AF:

0.00992

AC:

14484

AN:

1460786

Hom.:

Cov.:

AF XY:

0.00955

AC XY:

6942

AN XY:

726628

show subpopulations

Gnomad4 AFR exome

AF:

0.00158

Gnomad4 AMR exome

AF:

0.00224

Gnomad4 ASJ exome

AF:

0.00180

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00199

Gnomad4 NFE exome

AF:

0.0122

Gnomad4 OTH exome

AF:

0.00936

GnomAD4 genome

AF:

0.00532

AC:

811

AN:

152374

Hom.:

Cov.:

AF XY:

0.00486

AC XY:

362

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00204

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00980

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00868

Hom.:

Bravo

AF:

0.00555

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.0100

AC:

ExAC

AF:

0.00527

AC:

640

EpiCase

AF:

0.0104

EpiControl

AF:

0.00984

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MC1R p.Asp84Glu variant was identified in 15 of 302 proband chromosomes (frequency: 0.0497) from individuals or families with melanoma and was identified in 2 of 298 control chromosomes (frequency: 0.0067) from healthy individuals (Valverde_2016_PMDI:8894704; Matichard_2004_PMID:14757863). The D84E variant has also been associated with red hair and fair skin (Raimondi_2008_PMID:18366057; Beaumont_2007_PMID:17616515). The variant was identified in dbSNP (ID: rs1805006) and ClinVar (classified as benign by Invitae, likely benign by Illumina and likely pathogenic by GeneDx); the variant was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 1440 of 280086 chromosomes (7 homozygous) at a frequency of 0.005141 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 1222 of 127966 chromosomes (freq: 0.009549), Other in 38 of 7140 chromosomes (freq: 0.005322), Latino in 71 of 35352 chromosomes (freq: 0.002008), Ashkenazi Jewish in 20 of 10324 chromosomes (freq: 0.001937), European (Finnish) in 47 of 24950 chromosomes (freq: 0.001884) and African in 42 of 24236 chromosomes (freq: 0.001733), while the variant was not observed in the East Asian or South Asian populations. In vitro expression studies revealed that the D84E variant has reduced cell surface expression and corresponding impairment in cAMP coupling which is associated with the red hair and fair skin pigmentation phenotype (Beaumont_2007_PMID: 17616515). The p.Asp84 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Mar 11, 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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MC1R: PP3, BS2 -

Aug 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in association with increased risk for UV exposure-related melanoma (Puig-Butille et al., 2013; Raimondi et al., 2008); Published functional studies demonstrate a damaging effect: reduced cell surface expression and decreased ability to elevate intracellular cAMP levels (Beaumont et al., 2007); This variant is associated with the following publications: (PMID: 23647022, 11875032, 18366057, 18657399, 22572819, 19924138, 8894704, 26103569, 19656326, 24335900, 17616515, 29405243, 27755135, 30872112, 29795986, 29898205, 30657907, 14757863, 29583157, 29316344, 25159867, 30531825, 31382929, 30414346, 14709592) -

Melanoma, cutaneous malignant, susceptibility to, 5

Benign:2Other:1

Oct 01, 1996

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 02, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

.;D;D;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.74

T;.;T;T

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

3.6

.;H;H;.

PROVEAN

Uncertain

-3.7

D;.;D;N

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0010

D;.;D;D

Polyphen

0.99

.;D;D;.

Vest4

0.97

MutPred

0.24

Gain of disorder (P = 0.336);Gain of disorder (P = 0.336);Gain of disorder (P = 0.336);Gain of disorder (P = 0.336);

MVP

0.94

MPC

0.11

ClinPred

0.069

GERP RS

2.9

Varity_R

0.91

gMVP

0.65

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