rs777024553

Variant names:

• chr16-89919506-C-G
• rs777024553
• NM_002386.4:c.248C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-89919506-C-G
• chr16-89919506-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002386.4(MC1R):​c.248C>G​(p.Ser83Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S83P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.83
• Publications: 0 publications found

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]

ENSG00000198211 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC1R	NM_002386.4	c.248C>G	p.Ser83Trp	missense_variant	Exon 1 of 1	ENST00000555147.2	NP_002377.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MC1R	ENST00000555147.2	c.248C>G	p.Ser83Trp	missense_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1
ENSG00000198211	ENST00000556922.1	c.248C>G	p.Ser83Trp	missense_variant	Exon 1 of 5	2		ENSP00000451560.1
MC1R	ENST00000555427.1	c.248C>G	p.Ser83Trp	missense_variant	Exon 3 of 4	5		ENSP00000451760.1
MC1R	ENST00000639847.1	c.248C>G	p.Ser83Trp	missense_variant	Exon 3 of 3	5		ENSP00000492011.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	.;D;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;.;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.9	.;H;H;.
PhyloP100		7.8
PROVEAN	Pathogenic	-5.1	D;.;D;N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0010	D;.;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.81
MutPred		0.69		Loss of catalytic residue at S83 (P = 0.1146);Loss of catalytic residue at S83 (P = 0.1146);Loss of catalytic residue at S83 (P = 0.1146);Loss of catalytic residue at S83 (P = 0.1146);
MVP		0.81
MPC		0.14
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		-0.0036	Neutral
Varity_R		0.92
gMVP		0.76

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

Other links and lift over

dbSNP: rs777024553; hg19: chr16-89985914;