rs2228478

Variant names:

• chr16-89920200-A-G
• rs2228478
• NM_002386.4:c.942A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002386.4(MC1R):​c.942A>G​(p.Thr314Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,613,248 control chromosomes in the GnomAD database, including 19,574 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4915 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14659 hom.)
• Consequence: MC1R NM_002386.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.194
• Publications: 66 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-89920200-A-G is Benign according to our data. Variant chr16-89920200-A-G is described in ClinVar as Benign. ClinVar VariationId is 258655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.194 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MC1R	NM_002386.4	c.942A>G	p.Thr314Thr	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.942A>G	p.Thr314Thr	synonymous_variant	Exon 1 of 1	6	NM_002386.4	ENSP00000451605.1
ENSG00000198211	ENST00000556922.1	c.942A>G	p.Thr314Thr	synonymous_variant	Exon 1 of 5	2		ENSP00000451560.1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31298 AN: 152080 Hom.: 4896 Cov.: 33

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0841

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.0806

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.143 AC: 35535 AN: 248648 AF XY: 0.140

Gnomad AFR exome AF: 0.451

Gnomad AMR exome AF: 0.0825

Gnomad ASJ exome AF: 0.0805

Gnomad EAS exome AF: 0.277

Gnomad FIN exome AF: 0.0816

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.127 AC: 185131 AN: 1461050 Hom.: 14659 Cov.: 34 AF XY: 0.127 AC XY: 92463 AN XY: 726836

African (AFR) AF: 0.453 AC: 15160 AN: 33466

American (AMR) AF: 0.0825 AC: 3690 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0792 AC: 2069 AN: 26130

East Asian (EAS) AF: 0.187 AC: 7428 AN: 39688

South Asian (SAS) AF: 0.182 AC: 15728 AN: 86246

European-Finnish (FIN) AF: 0.0815 AC: 4349 AN: 53374

Middle Eastern (MID) AF: 0.105 AC: 605 AN: 5766

European-Non Finnish (NFE) AF: 0.114 AC: 126951 AN: 1111322

Other (OTH) AF: 0.152 AC: 9151 AN: 60348

GnomAD4 genome AF: 0.206 AC: 31355 AN: 152198 Hom.: 4915 Cov.: 33 AF XY: 0.200 AC XY: 14879 AN XY: 74434

African (AFR) AF: 0.437 AC: 18128 AN: 41486

American (AMR) AF: 0.106 AC: 1626 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0841 AC: 292 AN: 3472

East Asian (EAS) AF: 0.270 AC: 1398 AN: 5172

South Asian (SAS) AF: 0.204 AC: 986 AN: 4822

European-Finnish (FIN) AF: 0.0806 AC: 855 AN: 10612

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7641 AN: 68010

Other (OTH) AF: 0.166 AC: 350 AN: 2114

Alfa AF: 0.143 Hom.: 6486

Bravo AF: 0.215

Asia WGS AF: 0.254 AC: 883 AN: 3476

EpiCase AF: 0.107

EpiControl AF: 0.103

ClinVar

Significance: Benign

Submissions summary: Benign:5

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.2
DANN	Benign	0.48
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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: rs2228478; hg19: chr16-89986608; COSMIC: COSV59626392; COSMIC: COSV59626392;