rs2069391

Positions:

• chr12-55966094-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_006928.5(PMEL):​c.-51-32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 1,604,622 control chromosomes in the GnomAD database, including 4,920 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.075 (487 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4433 hom.)
• Consequence: PMEL NM_006928.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.103

Genes affected

PMEL (HGNC:10880): (premelanosome protein) This gene encodes a melanocyte-specific type I transmembrane glycoprotein. The encoded protein is enriched in melanosomes, which are the melanin-producing organelles in melanocytes, and plays an essential role in the structural organization of premelanosomes. This protein is involved in generating internal matrix fibers that define the transition from Stage I to Stage II melanosomes. This protein undergoes a complex pattern of prosttranslational processing and modification that is essential to the proper functioning of the protein. A secreted form of this protein that is released by proteolytic ectodomain shedding may be used as a melanoma-specific serum marker. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2011]

PMEL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMEL	NM_006928.5	c.-51-32G>A		intron_variant			NP_008859.1
PMEL	NM_001200054.1	c.-83G>A		upstream_gene_variant			NP_001186983.1
PMEL	NM_001320121.1	c.-83G>A		upstream_gene_variant			NP_001307050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMEL	ENST00000548493.5	c.-51-32G>A		intron_variant		2		ENSP00000447374.1
PMEL	ENST00000552882.5	c.-51-32G>A		intron_variant		5		ENSP00000449690.1
PMEL	ENST00000549418.5	c.-51-32G>A		intron_variant		4		ENSP00000446633.1

Frequencies

GnomAD3 genomes AF: 0.0746 AC: 11347 AN: 152162 Hom.: 486 Cov.: 32

Gnomad AFR AF: 0.0885

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.0535

Gnomad ASJ AF: 0.0769

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.0575

Gnomad FIN AF: 0.0689

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0779

Gnomad OTH AF: 0.0683

GnomAD4 exome AF: 0.0760 AC: 110376 AN: 1452342 Hom.: 4433 Cov.: 30 AF XY: 0.0750 AC XY: 54209 AN XY: 722314

Gnomad4 AFR exome AF: 0.0917

Gnomad4 AMR exome AF: 0.0541

Gnomad4 ASJ exome AF: 0.0750

Gnomad4 EAS exome AF: 0.00437

Gnomad4 SAS exome AF: 0.0566

Gnomad4 FIN exome AF: 0.0738

Gnomad4 NFE exome AF: 0.0807

Gnomad4 OTH exome AF: 0.0740

GnomAD4 genome AF: 0.0745 AC: 11348 AN: 152280 Hom.: 487 Cov.: 32 AF XY: 0.0737 AC XY: 5491 AN XY: 74456

Gnomad4 AFR AF: 0.0883

Gnomad4 AMR AF: 0.0534

Gnomad4 ASJ AF: 0.0769

Gnomad4 EAS AF: 0.00522

Gnomad4 SAS AF: 0.0575

Gnomad4 FIN AF: 0.0689

Gnomad4 NFE AF: 0.0779

Gnomad4 OTH AF: 0.0666

Alfa AF: 0.0748 Hom.: 486

Bravo AF: 0.0740

Asia WGS AF: 0.0290 AC: 100 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.89

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: rs2069391; hg19: chr12-56359878;