chr12-55726760-C-G

Position:

• chr12-55726760-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001780.6(CD63):​c.366G>C​(p.Gln122His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CD63 NM_001780.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.290

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29434288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD63	NM_001780.6	c.366G>C	p.Gln122His	missense_variant	5/8	ENST00000257857.9	NP_001771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD63	ENST00000257857.9	c.366G>C	p.Gln122His	missense_variant	5/8	1	NM_001780.6	ENSP00000257857.4
CD63	ENST00000552067.5	c.87G>C	p.Gln29His	missense_variant	3/6	5		ENSP00000449684.1
CD63	ENST00000550050.5	n.*32G>C		non_coding_transcript_exon_variant	5/8	5		ENSP00000449435.1
CD63	ENST00000550050.5	n.*32G>C		3_prime_UTR_variant	5/8	5		ENSP00000449435.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

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

Sep 16, 2021

The c.366G>C (p.Q122H) alteration is located in exon 5 (coding exon 4) of the CD63 gene. This alteration results from a G to C substitution at nucleotide position 366, causing the glutamine (Q) at amino acid position 122 to be replaced by a histidine (H). 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	Uncertain	0.34
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.21	T;D;T;T;.;D;D;D;.;.;.;.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.69	.;T;.;T;.;.;.;.;T;T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	2.0	.;M;.;.;.;M;M;M;.;.;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;T;.;T;T
Polyphen		0.73	.;P;.;.;.;P;P;P;.;.;.;.;.
Vest4		0.13
MutPred		0.62		.;Gain of catalytic residue at R120 (P = 0.0012);.;.;.;Gain of catalytic residue at R120 (P = 0.0012);Gain of catalytic residue at R120 (P = 0.0012);Gain of catalytic residue at R120 (P = 0.0012);.;.;Gain of catalytic residue at R120 (P = 0.0012);Gain of catalytic residue at R120 (P = 0.0012);Gain of catalytic residue at R120 (P = 0.0012);
MVP		0.83
MPC		0.96
ClinPred		0.30	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr12-56120544;