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. The variant received -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:5
• Conservation: PhyloP100: -0.174
• Publications: 16 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 -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 Benign/Likely_benign. ClinVar VariationId is 239161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.174 with no splicing effect.
• BS2: High AC in GnomAd4 at 405 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.699G>A	p.Gln233Gln	synonymous	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.699G>A	p.Gln233Gln	synonymous	Exon 1 of 1	ENSP00000451605.1	Q01726
	ENSG00000198211	ENST00000556922.1	TSL:2	c.699G>A	p.Gln233Gln	synonymous	Exon 1 of 5	ENSP00000451560.1	A0A0B4J269
	MC1R	ENST00000555427.1	TSL:5	c.699G>A	p.Gln233Gln	synonymous	Exon 3 of 4	ENSP00000451760.1	G3V4F0

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

GnomAD2 exomes AF: 0.00451 AC: 1114 AN: 246754 AF XY: 0.00529

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 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

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00273 AC: 122 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00325 AC: 85 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0150 AC: 1291 AN: 86258

European-Finnish (FIN) AF: 0.000251 AC: 13 AN: 51804

Middle Eastern (MID) AF: 0.00693 AC: 40 AN: 5768

European-Non Finnish (NFE) AF: 0.00297 AC: 3303 AN: 1111850

Other (OTH) AF: 0.00295 AC: 178 AN: 60356

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

African (AFR) AF: 0.000385 AC: 16 AN: 41594

American (AMR) AF: 0.00196 AC: 30 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00378 AC: 257 AN: 68036

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.5
DANN	Benign	0.74
PhyloP100		-0.17
Mutation Taster		=100/0	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: rs146544450; hg19: chr16-89986365; COSMIC: COSV59625683; COSMIC: COSV59625683;