rs200215218
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_002386.4(MC1R):c.766C>T(p.Pro256Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,613,616 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 1 hom. )
Consequence
MC1R
NM_002386.4 missense
NM_002386.4 missense
Scores
10
7
1
Clinical Significance
Conservation
PhyloP100: 7.84
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAd4 at 13 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MC1R | NM_002386.4 | c.766C>T | p.Pro256Ser | missense_variant | 1/1 | ENST00000555147.2 | NP_002377.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MC1R | ENST00000555147.2 | c.766C>T | p.Pro256Ser | missense_variant | 1/1 | NM_002386.4 | ENSP00000451605 | P1 | ||
ENST00000554623.1 | n.788G>A | non_coding_transcript_exon_variant | 2/2 | 3 | ||||||
MC1R | ENST00000555427.1 | c.766C>T | p.Pro256Ser | missense_variant | 3/4 | 5 | ENSP00000451760 | |||
MC1R | ENST00000639847.1 | c.766C>T | p.Pro256Ser | missense_variant | 3/3 | 5 | ENSP00000492011 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152224Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000225 AC: 56AN: 248940Hom.: 0 AF XY: 0.000289 AC XY: 39AN XY: 135084
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GnomAD4 exome AF: 0.000137 AC: 200AN: 1461392Hom.: 1 Cov.: 35 AF XY: 0.000164 AC XY: 119AN XY: 726960
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GnomAD4 genome AF: 0.0000854 AC: 13AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74374
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Melanoma, cutaneous malignant, susceptibility to, 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 06, 2023 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 256 of the MC1R protein (p.Pro256Ser). This variant is present in population databases (rs200215218, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with melanoma (PMID: 15998953, 19799798, 23647022, 24982914, 25284244). ClinVar contains an entry for this variant (Variation ID: 470711). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MC1R protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Tyrosinase-positive oculocutaneous albinism Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.020%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.77; 3Cnet: 0.09). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MC1R- related disorder (PMID: 11933208). However, the evidence of pathogenicity is insufficient at this time and classified as auncertain significancein ClinVar (ClinVar ID: VCV000470711). Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. - |
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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;H;H;.
MutationTaster
Benign
D;D
PROVEAN
Pathogenic
D;.;D;N
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;D
Sift4G
Uncertain
D;.;D;D
Polyphen
1.0
.;D;D;.
Vest4
MVP
MPC
0.13
ClinPred
D
GERP RS
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gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at