rs2069391

Variant names:

• chr12-55966094-C-T
• rs2069391
• NM_006928.5:c.-51-32G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 18 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PMEL	NM_001384361.1	c.-83G>A		upstream_gene_variant		ENST00000548747.6	NP_001371290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMEL	ENST00000548747.6	c.-83G>A		upstream_gene_variant		1	NM_001384361.1	ENSP00000448828.1

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

African (AFR) AF: 0.0917 AC: 3026 AN: 32994

American (AMR) AF: 0.0541 AC: 2338 AN: 43200

Ashkenazi Jewish (ASJ) AF: 0.0750 AC: 1924 AN: 25648

East Asian (EAS) AF: 0.00437 AC: 173 AN: 39610

South Asian (SAS) AF: 0.0566 AC: 4834 AN: 85362

European-Finnish (FIN) AF: 0.0738 AC: 3920 AN: 53138

Middle Eastern (MID) AF: 0.0698 AC: 365 AN: 5232

European-Non Finnish (NFE) AF: 0.0807 AC: 89363 AN: 1107222

Other (OTH) AF: 0.0740 AC: 4433 AN: 59936

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

African (AFR) AF: 0.0883 AC: 3668 AN: 41550

American (AMR) AF: 0.0534 AC: 817 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 267 AN: 3472

East Asian (EAS) AF: 0.00522 AC: 27 AN: 5176

South Asian (SAS) AF: 0.0575 AC: 278 AN: 4832

European-Finnish (FIN) AF: 0.0689 AC: 731 AN: 10614

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0779 AC: 5300 AN: 68016

Other (OTH) AF: 0.0666 AC: 141 AN: 2116

Alfa AF: 0.0736 Hom.: 728

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
PhyloP100		0.10
PromoterAI		0.00060	Neutral
Mutation Taster		=297/3	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: rs2069391; hg19: chr12-56359878;