chr16-89919813-C-T
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_002386.4(MC1R):c.555C>T(p.His185=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,607,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00034 ( 0 hom. )
Consequence
MC1R
NM_002386.4 synonymous
NM_002386.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.34
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -17 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 16-89919813-C-T is Benign according to our data. Variant chr16-89919813-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 321431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89919813-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=1.34 with no splicing effect.
BS2
High AC in GnomAd4 at 46 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MC1R | NM_002386.4 | c.555C>T | p.His185= | synonymous_variant | 1/1 | ENST00000555147.2 | NP_002377.4 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MC1R | ENST00000555147.2 | c.555C>T | p.His185= | synonymous_variant | 1/1 | NM_002386.4 | ENSP00000451605 | P1 | ||
| MC1R | ENST00000555427.1 | c.555C>T | p.His185= | synonymous_variant | 3/4 | 5 | ENSP00000451760 | |||
| MC1R | ENST00000639847.1 | c.555C>T | p.His185= | synonymous_variant | 3/3 | 5 | ENSP00000492011 | P1 | ||
| ENST00000554623.1 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes 0.000302 AC: 46AN: 152248Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000254 AC: 62AN: 244260Hom.: 0 AF XY: 0.000195 AC XY: 26AN XY: 133134
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GnomAD4 exome AF: 0.000339 AC: 494AN: 1455208Hom.: 0 Cov.: 35 AF XY: 0.000318 AC XY: 230AN XY: 724186
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GnomAD4 genome 0.000302 AC: 46AN: 152366Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25AN XY: 74496
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Melanoma, cutaneous malignant, susceptibility to, 5 Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | - - |
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at