rs181269865

chr16-89920050-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002386.4(MC1R):c.792C>T(p.Ile264=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,613,824 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: MC1R NM_002386.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.152

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 16-89920050-C-T is Benign according to our data. Variant chr16-89920050-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 321440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89920050-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.152 with no splicing effect.
• BS2: High AC in GnomAd at 299 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MC1R	NM_002386.4	c.792C>T	p.Ile264=	synonymous_variant	1/1	ENST00000555147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MC1R	ENST00000555147.2	c.792C>T	p.Ile264=	synonymous_variant	1/1		NM_002386.4	P1
	ENST00000554623.1	n.762G>A		non_coding_transcript_exon_variant	2/2	3
MC1R	ENST00000555427.1	c.792C>T	p.Ile264=	synonymous_variant	3/4	5
MC1R	ENST00000639847.1	c.792C>T	p.Ile264=	synonymous_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 299 AN: 152236 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00235 AC: 585 AN: 249152 Hom.: 3 AF XY: 0.00232 AC XY: 314 AN XY: 135174

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.00162

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00152 AC: 2228 AN: 1461470 Hom.: 5 Cov.: 35 AF XY: 0.00154 AC XY: 1116 AN XY: 726988

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000800

Gnomad4 FIN exome AF: 0.0140

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00196 AC: 298 AN: 152354 Hom.: 3 Cov.: 33 AF XY: 0.00282 AC XY: 210 AN XY: 74500

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000710

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2021	This variant is associated with the following publications: (PMID: 23360207, 28059796, 27924526, 11254446, 24982914, 15221796, 20629734, 16172233, 11511307) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	MC1R: BP4, BP7 -

Melanoma, cutaneous malignant, susceptibility to, 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	1.1
Dann	Benign	0.84

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

LitVar

Other links and lift over

dbSNP: rs181269865; hg19: chr16-89986458;