12-55726123-C-T

Position:

• chr12-55726123-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001780.6(CD63):​c.565G>A​(p.Glu189Lys) variant causes a missense, splice region 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. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CD63 NM_001780.6 missense, splice_region
• Scores: Splicing: ADA: 0.00007253
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.578

Genes affected

CD63 (HGNC:1692): (CD63 molecule) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. The encoded protein is a cell surface glycoprotein that is known to complex with integrins. It may function as a blood platelet activation marker. Deficiency of this protein is associated with Hermansky-Pudlak syndrome. Also this gene has been associated with tumor progression. Alternative splicing results in multiple transcript variants encoding different protein isoforms. [provided by RefSeq, Apr 2012]

CD63 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11056152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD63	NM_001780.6	c.565G>A	p.Glu189Lys	missense_variant, splice_region_variant	6/8	ENST00000257857.9	NP_001771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD63	ENST00000257857.9	c.565G>A	p.Glu189Lys	missense_variant, splice_region_variant	6/8	1	NM_001780.6	ENSP00000257857.4
CD63	ENST00000552067.5	c.286G>A	p.Glu96Lys	missense_variant, splice_region_variant	4/6	5		ENSP00000449684.1
CD63	ENST00000550050.5	n.*231G>A		splice_region_variant, non_coding_transcript_exon_variant	6/8	5		ENSP00000449435.1
CD63	ENST00000550050.5	n.*231G>A		3_prime_UTR_variant	6/8	5		ENSP00000449435.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The c.565G>A (p.E189K) alteration is located in exon 6 (coding exon 5) of the CD63 gene. This alteration results from a G to A substitution at nucleotide position 565, causing the glutamic acid (E) at amino acid position 189 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	5.0
DANN	Benign	0.76
DEOGEN2	Benign	0.16	T;T;T;T;.;T;T;T;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.76	.;T;.;T;.;.;.;.;T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.71	.;N;.;.;.;N;N;N;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.67	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T;T;T;T;T;T;.;T
Polyphen		0.0010	.;B;.;.;.;B;B;B;.;.;.;.
Vest4		0.10
MutPred		0.55		.;Gain of catalytic residue at K188 (P = 0.001);.;.;.;Gain of catalytic residue at K188 (P = 0.001);Gain of catalytic residue at K188 (P = 0.001);Gain of catalytic residue at K188 (P = 0.001);.;.;Gain of catalytic residue at K188 (P = 0.001);Gain of catalytic residue at K188 (P = 0.001);
MVP		0.51
MPC		0.48
ClinPred		0.11	T
GERP RS		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000073
dbscSNV1_RF	Benign	0.0
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-56119907; COSMIC: COSV105089683; COSMIC: COSV105089683;