NM_002386.4:c.900C>T

Variant names:

• chr16-89920158-C-T
• rs3212367
• NM_002386.4:c.900C>T
• MC1R p.Phe300Phe

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -15 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_StrongBP7

The NM_002386.4(MC1R):c.900C>T (p.Phe300Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00317 (AC=5,114) in the gnomAD database across 1,614,052 control chromosomes, including 164 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0583. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (92 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (72 hom.)
• Consequence: MC1R NM_002386.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.73
• Publications: 8 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]

MC1R Gene-Disease associations (from GenCC):

• oculocutaneous albinism type 2

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia

ENSG00000198211 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -15 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.0583 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002386.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MC1R NM_002386.4	MANE Select	c.900C>T p.Phe300Phe	synonymous	Exon 1 of 1	Prot: NP_002377.4

MC1R NM_002386.4

MANE Select

HGVSc / HGVSpc.900C>Tp.Phe300Phe

Exon rankExon 1 of 1

synonymous

Prot: NP_002377.4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MC1R ENST00000555147.2	TSL:6MANE Select	c.900C>T p.Phe300Phe	synonymous	Exon 1 of 1	Prot: ENSP00000451605.1 UniProt:
	ENSG00000198211 ENST00000556922.1	TSL:2	c.900C>T p.Phe300Phe	synonymous	Exon 1 of 5	Prot: ENSP00000451560.1 UniProt:
	MC1R ENST00000555427.1	TSL:5	c.900C>T p.Phe300Phe	synonymous	Exon 3 of 4	Prot: ENSP00000451760.1 UniProt:

MC1R ENST00000555147.2

TSL:6MANE Select

HGVSc / HGVSpc.900C>Tp.Phe300Phe

Exon rankExon 1 of 1

synonymous

Prot: ENSP00000451605.1UniProt: Q01726

ENSG00000198211 ENST00000556922.1

TSL:2

HGVSc / HGVSpc.900C>Tp.Phe300Phe

Exon rankExon 1 of 5

synonymous

Prot: ENSP00000451560.1UniProt: A0A0B4J269

MC1R ENST00000555427.1

TSL:5

HGVSc / HGVSpc.900C>Tp.Phe300Phe

Exon rankExon 3 of 4

synonymous

Prot: ENSP00000451760.1UniProt: G3V4F0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0174	AC:2646	Hom:92	AN:152254	Cov:33
GnomAD2 exomes	AF: 0.00434	AC:1082	Hom:	AN:249048	Cov:
GnomAD4 exome	AF: 0.00168	AC:2462	Hom:72	AN:1461680	Cov:34
GnomAD4 genome	AF: 0.0174	AC:2652	Hom:92	AN:152372	Cov:33
TOPMed (Bravo)	AF: 0.0198	AC:5241	Hom:158	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0118	AC:1233	Hom:36	AN:104474	Cov:
Local & regional cohorts 7 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0115	AC:27	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0163	AC:206	Hom:	AN:12628	Cov:
GenomeAsia100K	AF: 0.00318	AC:11	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.00570	AC:1	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122574	Cov:
Turkish Variome	AF: 0.000357	AC:2	Hom:0	AN:5132	Cov:
UK10K	AF: 0.000132	AC:1	Hom:	AN:7562	Cov:

Showing 13 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000693	2	28844
Epi25(Epilepsy)	0.00543	228	41958	0.00592	396	66888
SCHEMA(Schizophrenia)	0.0124	1478	118730	0.0137	2533	184970

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Melanoma, cutaneous malignant, susceptibility to, 5 (2)
-	-	1	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.92
GPN-Star LLR	N/A	-2.4
GPN-Star score	N/A	2.4
Mutation Taster	N/A	98/2	polymorphism (auto)
PhyloP100	Benign	1.7

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3212367;

hg19: chr16-89986566;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar