12-55955822-C-T

Variant names:

• chr12-55955822-C-T
• rs76045902
• NM_001384361.1:c.1513G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384361.1(PMEL):​c.1513G>A​(p.Gly505Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00428 in 1,614,050 control chromosomes in the GnomAD database, including 269 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G505D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (146 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (123 hom.)
• Consequence: PMEL NM_001384361.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.10
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014944077).
• BP6: Variant 12-55955822-C-T is Benign according to our data. Variant chr12-55955822-C-T is described in ClinVar as Benign. ClinVar VariationId is 789322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0789 is higher than 0.05.

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.1513G>A	p.Gly505Ser	missense	Exon 8 of 11	NP_001371290.1	P40967-1
	PMEL	NM_001200054.1		c.1513G>A	p.Gly505Ser	missense	Exon 8 of 11	NP_001186983.1	P40967-2
	PMEL	NM_006928.5		c.1513G>A	p.Gly505Ser	missense	Exon 9 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.1513G>A	p.Gly505Ser	missense	Exon 8 of 11	ENSP00000448828.1	P40967-1
	PMEL	ENST00000449260.6	TSL:1	c.1513G>A	p.Gly505Ser	missense	Exon 8 of 11	ENSP00000402758.2	P40967-2
	PMEL	ENST00000550762.1	TSL:1	n.479G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3553 AN: 152112 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.0810

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00607 AC: 1526 AN: 251438 AF XY: 0.00425

Gnomad AFR exome AF: 0.0840

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00229 AC: 3345 AN: 1461820 Hom.: 123 Cov.: 31 AF XY: 0.00189 AC XY: 1371 AN XY: 727220

African (AFR) AF: 0.0819 AC: 2742 AN: 33478

American (AMR) AF: 0.00378 AC: 169 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1111962

Other (OTH) AF: 0.00447 AC: 270 AN: 60394

GnomAD4 genome AF: 0.0235 AC: 3570 AN: 152230 Hom.: 146 Cov.: 32 AF XY: 0.0232 AC XY: 1730 AN XY: 74442

African (AFR) AF: 0.0812 AC: 3370 AN: 41512

American (AMR) AF: 0.00961 AC: 147 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68020

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.00859 Hom.: 76

Bravo AF: 0.0268

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0842 AC: 371

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00780 AC: 947

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	10
DANN	Benign	0.68
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N
PhyloP100		1.1
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.61	N
REVEL	Benign	0.043
Sift	Benign	0.87	T
Sift4G	Benign	0.64	T
Polyphen		0.0010	B
Vest4		0.16
MVP		0.15
MPC		0.12
ClinPred		0.0026	T
GERP RS		3.0
Varity_R		0.043
gMVP		0.30
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs76045902; hg19: chr12-56349606; COSMIC: COSV99045604; COSMIC: COSV99045604;