chr16-89919436-G-T

Variant names:

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.178G>T(p.Val60Leu) variant causes a missense change. The variant allele was found at a frequency of 0.106 in 1,613,224 control chromosomes in the GnomAD database, including 11,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.080 ( 782 hom., cov: 33)

Exomes 𝑓: 0.11 ( 10454 hom. )

Consequence

MC1R
NM_002386.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 3.88

Publications

255 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=0.0017996728).

BP6

Variant 16-89919436-G-T is Benign according to our data. Variant chr16-89919436-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 14311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 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.178G>T	p.Val60Leu	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.178G>T	p.Val60Leu	missense	Exon 1 of 1	ENSP00000451605.1	Q01726
ENSG00000198211	ENST00000556922.1	TSL:2	c.178G>T	p.Val60Leu	missense	Exon 1 of 5	ENSP00000451560.1	A0A0B4J269
MC1R	ENST00000555427.1	TSL:5	c.178G>T	p.Val60Leu	missense	Exon 3 of 4	ENSP00000451760.1	G3V4F0

Frequencies

GnomAD3 genomes

AF:

0.0803

AC:

12226

AN:

152162

Hom.:

782

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0207

Gnomad AMI

AF:

0.165

Gnomad AMR

AF:

0.0817

Gnomad ASJ

AF:

0.304

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.0560

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.111

GnomAD2 exomes

AF:

0.0860

AC:

21392

AN:

248798

AF XY:

0.0852

show subpopulations

Gnomad AFR exome

AF:

0.0178

Gnomad AMR exome

AF:

0.0636

Gnomad ASJ exome

AF:

0.288

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.0571

Gnomad NFE exome

AF:

0.122

Gnomad OTH exome

AF:

0.116

GnomAD4 exome

AF:

0.109

AC:

159401

AN:

1460944

Hom.:

10454

Cov.:

AF XY:

0.106

AC XY:

77330

AN XY:

726744

show subpopulations

African (AFR)

AF:

0.0179

AC:

599

AN:

33480

American (AMR)

AF:

0.0661

AC:

2958

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

7633

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0124

AC:

1068

AN:

86258

European-Finnish (FIN)

AF:

0.0585

AC:

3079

AN:

52656

Middle Eastern (MID)

AF:

0.101

AC:

584

AN:

5768

European-Non Finnish (NFE)

AF:

0.123

AC:

136292

AN:

1111862

Other (OTH)

AF:

0.119

AC:

7187

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

9428

18855

28283

37710

47138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4834

9668

14502

19336

24170

<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:

0.0803

AC:

12226

AN:

152280

Hom.:

782

Cov.:

AF XY:

0.0751

AC XY:

5589

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0207

AC:

861

AN:

41578

American (AMR)

AF:

0.0815

AC:

1247

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

1056

AN:

3468

East Asian (EAS)

AF:

0.00155

AC:

AN:

5170

South Asian (SAS)

AF:

0.0116

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0560

AC:

594

AN:

10614

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.117

AC:

7985

AN:

68008

Other (OTH)

AF:

0.111

AC:

234

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

561

1123

1684

2246

2807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.112

Hom.:

3846

Bravo

AF:

0.0830

TwinsUK

AF:

0.118

AC:

438

ALSPAC

AF:

0.124

AC:

478

ESP6500AA

AF:

0.0226

AC:

ESP6500EA

AF:

0.133

AC:

1137

ExAC

AF:

0.0826

AC:

10010

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.142

EpiControl

AF:

0.139

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (2)

Malignant tumor of breast (1)

not specified (1)

Tyrosinase-positive oculocutaneous albinism;C1849452:SKIN/HAIR/EYE PIGMENTATION, VARIATION IN, 2;C2751295:Melanoma, cutaneous malignant, susceptibility to, 5;C2751296:Increased analgesia from kappa-opioid receptor agonist, female-specific (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

PhyloP100

3.9

PROVEAN

Benign

-1.7

REVEL

Benign

0.16

Sift

Pathogenic

0.0

Sift4G

Benign

0.14

Polyphen

0.99

Vest4

0.48

MutPred

0.21

Loss of catalytic residue at V60 (P = 0.0973)

MPC

0.13

ClinPred

0.037

GERP RS

4.9

PromoterAI

0.00050

Neutral

(source)

Varity_R

0.53

gMVP

0.25

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over