rs3212366

Variant names:

• chr16-89919844-T-C
• rs3212366
• NM_002386.4:c.586T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-89919844-T-C
• chr16-89919844-T-G
• chr16-89919844-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002386.4(MC1R):​c.586T>C​(p.Phe196Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00192 in 1,606,684 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts 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. F196V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0094 (25 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: MC1R NM_002386.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.21
• Publications: 34 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007436037).
• BP6: Variant 16-89919844-T-C is Benign according to our data. Variant chr16-89919844-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 321433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00942 (1435/152310) while in subpopulation AFR AF = 0.0327 (1357/41562). AF 95% confidence interval is 0.0312. There are 25 homozygotes in GnomAd4. There are 667 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1435 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.586T>C	p.Phe196Leu	missense	Exon 1 of 1	NP_002377.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MC1R	ENST00000555147.2	TSL:6 MANE Select	c.586T>C	p.Phe196Leu	missense	Exon 1 of 1	ENSP00000451605.1	Q01726
	ENSG00000198211	ENST00000556922.1	TSL:2	c.586T>C	p.Phe196Leu	missense	Exon 1 of 5	ENSP00000451560.1	A0A0B4J269
	MC1R	ENST00000555427.1	TSL:5	c.586T>C	p.Phe196Leu	missense	Exon 3 of 4	ENSP00000451760.1	G3V4F0

Frequencies

GnomAD3 genomes AF: 0.00941 AC: 1432 AN: 152192 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00242 AC: 589 AN: 243276 AF XY: 0.00183

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000668

GnomAD4 exome AF: 0.00113 AC: 1649 AN: 1454374 Hom.: 28 Cov.: 35 AF XY: 0.00101 AC XY: 729 AN XY: 723736

African (AFR) AF: 0.0380 AC: 1271 AN: 33470

American (AMR) AF: 0.00134 AC: 60 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26122

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39694

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46398

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.000151 AC: 168 AN: 1111666

Other (OTH) AF: 0.00186 AC: 112 AN: 60304

GnomAD4 genome AF: 0.00942 AC: 1435 AN: 152310 Hom.: 25 Cov.: 33 AF XY: 0.00895 AC XY: 667 AN XY: 74490

African (AFR) AF: 0.0326 AC: 1357 AN: 41562

American (AMR) AF: 0.00340 AC: 52 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68014

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00509 Hom.: 8

Bravo AF: 0.0111

ESP6500AA AF: 0.0309 AC: 134

ESP6500EA AF: 0.000470 AC: 4

ExAC AF: 0.00297 AC: 360

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Melanoma, cutaneous malignant, susceptibility to, 5 (2)
-	-	1	MC1R-related disorder (1)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0074	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.2
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.065	T
Polyphen		1.0	D
Vest4		0.74
MutPred		0.29		Loss of helix (P = 0.3949)
MVP		0.69
MPC		0.13
ClinPred		0.074	T
GERP RS		4.6
Varity_R		0.69
gMVP		0.51
Mutation Taster		=80/20	polymorphism

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: rs3212366; hg19: chr16-89986252; COSMIC: COSV99043880; COSMIC: COSV99043880;