12-55957562-G-T

Variant names:

• chr12-55957562-G-T
• rs1052165
• NM_001384361.1:c.741C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP7

The NM_001384361.1(PMEL):​c.741C>A​(p.Pro247Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
• Consequence: PMEL NM_001384361.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24
• Publications: 29 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.244).
• BP7: Synonymous conserved (PhyloP=3.24 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384361.1. 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
	PMEL	NM_001384361.1	MANE Select	c.741C>A	p.Pro247Pro	synonymous	Exon 6 of 11	NP_001371290.1	P40967-1
	PMEL	NM_001200054.1		c.741C>A	p.Pro247Pro	synonymous	Exon 6 of 11	NP_001186983.1	P40967-2
	PMEL	NM_006928.5		c.741C>A	p.Pro247Pro	synonymous	Exon 7 of 12	NP_008859.1	P40967-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMEL	ENST00000548747.6	TSL:1 MANE Select	c.741C>A	p.Pro247Pro	synonymous	Exon 6 of 11	ENSP00000448828.1	P40967-1
	PMEL	ENST00000449260.6	TSL:1	c.741C>A	p.Pro247Pro	synonymous	Exon 6 of 11	ENSP00000402758.2	P40967-2
	PMEL	ENST00000548493.5	TSL:2	c.741C>A	p.Pro247Pro	synonymous	Exon 7 of 12	ENSP00000447374.1	P40967-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.2
DANN	Benign	0.85
PhyloP100		3.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1052165; hg19: chr12-56351346;