rs146544450

Variant names:

• chr16-89919957-G-A
• rs146544450
• NM_002386.4:c.699G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-89919957-G-A
• chr16-89919957-G-C

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.699G>A​(p.Gln233Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,612,432 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (32 hom.)
• Consequence: MC1R NM_002386.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.174

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

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-89919957-G-A is Benign according to our data. Variant chr16-89919957-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 239161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89919957-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.174 with no splicing effect.
• BS2: High AC in GnomAd4 at 405 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC1R	NM_002386.4	c.699G>A	p.Gln233Gln	synonymous_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.699G>A	p.Gln233Gln	synonymous_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1
ENSG00000198211	ENST00000556922.1	c.699G>A	p.Gln233Gln	synonymous_variant	Exon 1 of 5	2		ENSP00000451560.1

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 405 AN: 152240 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00451 AC: 1114 AN: 246754 Hom.: 9 AF XY: 0.00529 AC XY: 709 AN XY: 134100

Gnomad AFR exome AF: 0.000651

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00380

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0157

Gnomad FIN exome AF: 0.000143

Gnomad NFE exome AF: 0.00421

Gnomad OTH exome AF: 0.00316

GnomAD4 exome AF: 0.00346 AC: 5055 AN: 1460072 Hom.: 32 Cov.: 35 AF XY: 0.00394 AC XY: 2860 AN XY: 726362

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.000251

Gnomad4 NFE exome AF: 0.00297

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00266 AC: 405 AN: 152360 Hom.: 2 Cov.: 33 AF XY: 0.00262 AC XY: 195 AN XY: 74504

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00378

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00281 Hom.: 0

Bravo AF: 0.00222

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00551

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 02, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.5
DANN	Benign	0.74

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: rs146544450; hg19: chr16-89986365; COSMIC: COSV59625683; COSMIC: COSV59625683;