NM_002386.4:c.652G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_002386.4(MC1R):c.652G>A(p.Ala218Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,608,156 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A218G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00028 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

MC1R
NM_002386.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 2.19

Publications

7 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08498928).

BP6

Variant 16-89919910-G-A is Benign according to our data. Variant chr16-89919910-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 321437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 43 AD gene.

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.652G>A	p.Ala218Thr	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.652G>A	p.Ala218Thr	missense	Exon 1 of 1	ENSP00000451605.1	Q01726
ENSG00000198211	ENST00000556922.1	TSL:2	c.652G>A	p.Ala218Thr	missense	Exon 1 of 5	ENSP00000451560.1	A0A0B4J269
MC1R	ENST00000555427.1	TSL:5	c.652G>A	p.Ala218Thr	missense	Exon 3 of 4	ENSP00000451760.1	G3V4F0

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000210

AC:

AN:

242354

AF XY:

0.000181

show subpopulations

Gnomad AFR exome

AF:

0.000197

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000347

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000412

AC:

600

AN:

1455894

Hom.:

Cov.:

AF XY:

0.000420

AC XY:

304

AN XY:

724440

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33470

American (AMR)

AF:

0.0000448

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000325

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48072

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000485

AC:

539

AN:

1111520

Other (OTH)

AF:

0.000414

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

128

170

213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.000282

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41560

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68006

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000243

Hom.:

Bravo

AF:

0.000268

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000484

AC:

ESP6500EA

AF:

0.000358

AC:

ExAC

AF:

0.000182

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance: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 (1)

Melanoma, cutaneous malignant, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Benign

-0.064

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.021

MetaRNN

Benign

0.085

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.8

PhyloP100

2.2

PROVEAN

Benign

-1.7

REVEL

Benign

0.094

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.019

Polyphen

0.94

Vest4

0.073

MVP

0.50

MPC

0.028

ClinPred

0.021

GERP RS

2.9

Varity_R

0.16

gMVP

0.36

Mutation Taster

=82/18

polymorphism

(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