rs1805007

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is . The variant received -8 ACMG points: 0P and 8B. BA1

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. 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. R151H) has been classified as Uncertain significance.

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 P:1U:1B:8O:3

Conservation

PhyloP100: 4.96

Publications

506 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 Gene-Disease associations (from GenCC):

oculocutaneous albinism type 2
Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia

MC1R links:

ENSG00000198211 (HGNC:):

ENSG00000198211 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002386.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002386.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC1R	NM_002386.4	MANE Select	c.451C>T	p.Arg151Cys	missense	Exon 1 of 1	NP_002377.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MC1R	ENST00000555147.2	TSL:6 MANE Select	c.451C>T	p.Arg151Cys	missense	Exon 1 of 1	ENSP00000451605.1	Q01726
ENSG00000198211	ENST00000556922.1	TSL:2	c.451C>T	p.Arg151Cys	missense	Exon 1 of 5	ENSP00000451560.1	A0A0B4J269
MC1R	ENST00000555427.1	TSL:5	c.451C>T	p.Arg151Cys	missense	Exon 3 of 4	ENSP00000451760.1	G3V4F0

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

GnomAD2 exomes

AF:

0.0442

AC:

10719

AN:

242744

AF XY:

0.0447

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 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

African (AFR)

AF:

0.0111

AC:

371

AN:

33472

American (AMR)

AF:

0.0112

AC:

500

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0677

AC:

1768

AN:

26126

East Asian (EAS)

AF:

0.000705

AC:

AN:

39698

South Asian (SAS)

AF:

0.00400

AC:

345

AN:

86242

European-Finnish (FIN)

AF:

0.0665

AC:

3042

AN:

45774

Middle Eastern (MID)

AF:

0.00884

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0928

AC:

103222

AN:

1111742

Other (OTH)

AF:

0.0643

AC:

3875

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

6668

13336

20003

26671

33339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3940

7880

11820

15760

19700

<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:

0.0462

AC:

7045

AN:

152352

Hom.:

229

Cov.:

AF XY:

0.0444

AC XY:

3304

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0148

AC:

615

AN:

41588

American (AMR)

AF:

0.0167

AC:

256

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0746

AC:

259

AN:

3472

East Asian (EAS)

AF:

0.000965

AC:

AN:

5182

South Asian (SAS)

AF:

0.00476

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0699

AC:

743

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0741

AC:

5039

AN:

68020

Other (OTH)

AF:

0.0270

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

363

726

1090

1453

1816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0589

Hom.:

435

Bravo

AF:

0.0434

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Melanoma, cutaneous malignant, susceptibility to, 5 (2)

not specified (2)

SKIN/HAIR/EYE PIGMENTATION, VARIATION IN, 2 (1)

ALBINISM, OCULOCUTANEOUS, TYPE II, MODIFIER OF (1)

Increased analgesia from kappa-opioid receptor agonist, female-specific (1)

Skin/hair/eye pigmentation 2, red hair/fair skin (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0076

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.5

PhyloP100

5.0

PROVEAN

Pathogenic

-7.4

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.013

Varity_R

0.76

gMVP

0.46

Mutation Taster

=90/10

disease causing (ClinVar)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over