12-55727261-G-A

Variant names:

• chr12-55727261-G-A
• rs977334983
• NM_001780.6:c.145C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001780.6(CD63):​c.145C>T​(p.Pro49Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CD63 NM_001780.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0640
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04497674).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001780.6. 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
	CD63	NM_001780.6	MANE Select	c.145C>T	p.Pro49Ser	missense	Exon 3 of 8	NP_001771.1	P08962-1
	CD63	NM_001257389.2		c.145C>T	p.Pro49Ser	missense	Exon 3 of 8	NP_001244318.1	P08962-1
	CD63	NM_001257390.2		c.145C>T	p.Pro49Ser	missense	Exon 3 of 8	NP_001244319.1	P08962-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD63	ENST00000257857.9	TSL:1 MANE Select	c.145C>T	p.Pro49Ser	missense	Exon 3 of 8	ENSP00000257857.4	P08962-1
	CD63	ENST00000552692.5	TSL:1	c.145C>T	p.Pro49Ser	missense	Exon 2 of 7	ENSP00000449337.1	P08962-1
	CD63	ENST00000552754.5	TSL:1	c.76C>T	p.Pro26Ser	missense	Exon 2 of 7	ENSP00000446807.1	P08962-2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152168 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461578 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727080

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111956

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152168 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74322

African (AFR) AF: 0.0000483 AC: 2 AN: 41432

American (AMR) AF: 0.000458 AC: 7 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.82
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.53	N
PhyloP100		-0.064
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	0.87	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.47		Gain of catalytic residue at A47 (P = 2e-04)
MVP		0.44
MPC		0.42
ClinPred		0.037	T
GERP RS		-3.6
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.028
gMVP		0.13
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs977334983; hg19: chr12-56121045; COSMIC: COSV108039626; COSMIC: COSV108039626;